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| United States Patent |
5,310,938
|
|
Brown
, et al.
|
May 10, 1994
|
Substituted arylpyrrole compounds
Abstract
This invention relates to methods and compositions for treating,
controlling, preventing and protecting warm-blooded animals from
infestation and infection by helminths, acarids and arthropod endo- and
ectoparasites by administering or applying to the animals a substituted
arylpyrrole compound.
| Inventors:
|
Brown; Dale G. (Hopewell, NJ);
Diehl; Robert E. (Yardley, PA);
Wright, Jr.; Donald P. (Hopewell Township, Mercer County, NJ);
Siddens, deceased; Jack K. (late of Des Moines, IA)
|
| Assignee:
|
American Cyanamid Company (Wayne, NJ)
|
| Appl. No.:
|
090863 |
| Filed:
|
July 13, 1993 |
| Current U.S. Class: |
548/557; 548/538; 548/558; 548/560; 548/561; 548/562 |
| Intern'l Class: |
C07D 207/34; C07D 207/42 |
| Field of Search: |
548/557,558,560,561,562,538
|
References Cited
U.S. Patent Documents
| 3428648 | Feb., 1969 | Umio et al. | 548/560.
|
| 3864491 | Apr., 1975 | Bailey | 548/557.
|
| 3963746 | Jun., 1976 | Bailey | 548/557.
|
| 4495358 | Jan., 1985 | Koyama et al. | 548/560.
|
| 4563472 | Jan., 1986 | Inouye et al. | 548/557.
|
| 4647576 | Mar., 1987 | Hoefle et al. | 548/560.
|
| 4705801 | Nov., 1987 | Martin et al. | 548/560.
|
| 4798901 | Jan., 1989 | Tessier et al. | 548/560.
|
| Foreign Patent Documents |
| 0080051 | Jun., 1983 | EP | 548/557.
|
| 0130149 | Jan., 1985 | EP | 548/557.
|
| 0182737 | May., 1986 | EP | 548/557.
|
| 0206523 | Dec., 1986 | EP | 548/560.
|
| 0206999 | Dec., 1986 | EP | 548/561.
|
| 0300688 | Jan., 1989 | EP | 548/557.
|
| 69-001528 | Jan., 1969 | JP | 548/561.
|
| 62-098562A | May., 1987 | JP | 548/560.
|
| 2111985 | Jul., 1983 | GB | 548/560.
|
Other References
CA 117(13):131061c Process . . . dihalomethanes, Kameswaran et al., p. 730,
1992.
CA 117(13):131062d Synthesis . . . Ketones, Kameswaran et al., p. 730,
1992.
CA 117(19):186674k Synergistic . . . derivatives, Lovell, p. 276, 1992.
CA 117(21):212309s Preparation . . . agents Kameswaran, p. 823, 1992.
CA 111(13):111037x Preparation . . . Molluscicides. Herman et al., p. 271,
1989.
CA 111(12):194576w Preparation . . . pesticides, Brown et al., p. 755,
1989.
CA 115(7):64243g Pyrrolomycin . . . Leukocytes, Masuda et al., p. 44, 1991.
CA 116(23):235429z Preparation . . . agents, Addor et al., p. 896, 1992.
CA 117(3):26331t Process . . . compounds, Lowen, p. 690, 1992.
CA 117(5):48330u Preparation . . . acaricides, Kameswaran et al, p. 910,
1992.
CA 117(13): 131058g diaryl-1H-Pyrrolecarbonitriles . . . acaricides, Kuhn
et al., p. 730, 1992.
Van Leusen et al., Tetrahedron Letters, 52, 5337-5340 (1972).
Tsuge et al., J. Org. Chem., 52, 2523-2530 (1987).
Benages et al., J. Org. Chem., 43 4273-4276 (1983).
|
Primary Examiner: Lee; Mary C.
Assistant Examiner: McKane; Joseph K.
Attorney, Agent or Firm: Hogan, Jr.; J. W.
Parent Case Text
This is a division of co-pending application Ser. No. 07/395,828, filed on
Aug. 18, 1989, which is a continuation-in-part of application Ser. No.
07/208,841, filed on Jun. 23, 1988, now U.S. Pat. No. 5,010,098, issued on
Apr. 23, 1991, which is a continuation-in-part of U.S. Ser. No.
07/079,545, filed on Jul. 29, 1987, now abandoned.
Claims
What is claimed:
1. A compound having the formula I structure:
##STR85##
wherein X is F, Cl, Br, I, or CF.sub.3 ;
Y is F, Cl, Br, I, or CF.sub.3 or CN;
W is CN or NO.sub.2 ;
A is H;
C.sub.1 -C.sub.4 alkyl optionally substituted with from one to three
halogen atoms,
one hydroxy,
one C.sub.1 -C.sub.4 alkoxy,
one C.sub.1 -C.sub.4 alkylthio,
one phenyl optionally substituted with C.sub.1 -C.sub.3 alkyl, C.sub.1
-C.sub.3 alkoxy, or one to three halogen atoms,
one phenoxy optionally substituted with one to three halogen atoms, or
one benzyloxy optionally substituted with one halogen substituent;
C.sub.1 -C.sub.4 carbalkoxymethyl;
C.sub.3 -C.sub.4 alkenyl optionally substituted with from one to three
halogen atoms;
cyano;
C.sub.3 -C.sub.4 alkynyl optionally substituted with one halogen atom;
di-(C.sub.1 -C.sub.4 alkyl) aminocarbonyl; or
C.sub.4 -C.sub.6 cycloalkylaminocarbonyl;
L is H, F, Cl, or Br;
M and R are each independently H, C.sub.1 -C.sub.3 alkyl,
C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 alkylthio, C.sub.1 -C.sub.3
alkylsulfinyl,
C.sub.1 -C.sub.3 alkylsulfonyl, cyano, F, Cl, Br, I, nitro,
CF.sub.3, R.sub.1 CF.sub.2 Z, R.sub.2 CO or NR.sub.3 R.sub.4, or when M and
R are on adjacent positions and taken with the carbon atoms to which they
are attached they may form a ring in which MR represents the structure:
--OCH.sub.2 O--, --OCF.sub.2 O-- or
##STR86##
Z is S(O).sub.n or O; R.sub.1 is H, F, CHF.sub.2, CHFCl, or CF.sub.3 ;
R.sub.2 is C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, or NR.sub.3
R.sub.4 ;
R.sub.3 is H or C.sub.1 -C.sub.3 alkyl;
R.sub.4 is H, C.sub.1 -C.sub.3 alkyl, or R.sub.5 CO;
R.sub.5 is H or C.sub.1 -C.sub.3 alkyl; and
n is an integer of 0, 1 or 2.
2. The compound according to claim 1, wherein A is hydrogen or C.sub.1
-C.sub.4 alkoxymethyl; W is CN or NO.sub.2 ; X and Y are each Cl,
CF.sub.3, or Br; R is F, Cl, Br, CF.sub.3, or OCF.sub.3 ; M is H, F, Cl,
or Br; and L is H or F.
3. The compound according to claim 1, wherein said compound has the
structure:
##STR87##
4. The compound according to claim 1, wherein said compound has the
structure:
##STR88##
5. The compound according to claim 1, wherein said compound has the
structure:
##STR89##
6. The compound according to claim 1, wherein said compound has the
structure:
##STR90##
7. The compound according to claim 1, wherein said compound has the
structure:
##STR91##
8. The compound according to claim 1, wherein said compound has the
structure:
##STR92##
9. The compound according to claim 1,
4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile.
10. The compound according to claim 1,
4,5-dichloro-2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyrrole-3-carbon
itrile.
11. The compound according to claim 1,
2,3-dichloro-4-nitro-5-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyrrole.
12. The compound according to claim 1,
2,3-dichloro-5-(3,4-dichlorophenyl)-4-nitropyrrole.
13. The compound according to claim 1,
4-bromo-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile.
14. The compound according to claim 1,
3,4-dibromo-5-(3,4-dichlorophenyl)pyrrole-2-carbonitrile.
15. The compound according to claim 1,
2,4-dibromo-5-(p-chlorophenyl)pyrrole-3-carbonitrile.
16. The compound according to claim 1,
5-(p-chlorophenyl)-3-(trifluoromethyl)pyrrole-2,4-dicarbonitrile.
17. The compound according to claim 1,
3-bromo-5-(3,4-dichlorophenyl)pyrrole-2,4-dicarbonitrile.
18. The compound according to claim 1,
4,5-dichloro-1-(ethoxymethyl)-2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl
)pyrrole-3-carbonitrile.
19. The compound according to claim 1,
4-bromo-2-(p-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-c
arbonitrile.
20. The compound according to claim 1,
4-bromo-2-(3,4-dichlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile.
Description
BACKGROUND OF THE INVENTION
It is an object of this invention to provide novel arylpyrrole compounds
and a method for treating, controlling, preventing and protecting
warm-blooded animals from infestation and infection by helminths, acarids
and arthropod endo and ectoparasites by administering thereto a
substituted arylpyrrole compound. It is also an object of this invention
to provide a method for protecting meat-producing and companion animals
from infestation by arthropod endo and ectoparasites by applying to said
animals a substituted arylpyrrole compound.
These and other objects will become more apparent from the detailed
description of the invention set forth below.
SUMMARY OF THE INVENTION
The present invention relates to novel arylpyrrole compounds and to methods
and compositions for treating, controlling, preventing and protecting
warm-blooded animals against infestation and infection by helminths,
acarids and arthropod endo- and ectoparasites, by orally or parenterally
administering to said animals or topically applying to said animals, an
anthelmintically, acaricidally or parasiticidally effective amount of a
substituted arylpyrrole compound.
The present invention is also directed to methods for preparing the
arylpyrrole compounds. The novel arylpyrrole compounds of the present
invention have the structural formula illustrated as formula I:
##STR1##
wherein X is F, Cl, Br, I, or CF.sub.3 ; Y is F, Cl, Br, I, CF.sub.3 or
CN; W is CN or NO.sub.2 and A is H; C.sub.1 -C.sub.4 alkyl optionally
substituted with from one to three halogen atoms, one hydroxy, one C.sub.1
-C.sub.4 alkoxy or one C.sub.1 -C.sub.4 alkylthio, one phenyl optionally
substituted with C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.3 alkoxy or with
one to three halogen atoms, one phenoxy optionally substituted with one to
three halogen atoms or one benzyloxy optionally substituted with one
halogen substituent; C.sub.1 -C.sub.4 carbalkoxymethyl; C.sub.3 -C.sub.4
alkenyl optionally substituted with from one to three halogen atoms;
cyano; C.sub.3 -C.sub.4 alkynyl optionally substituted with one halogen
atom; di-(C.sub.1 -C.sub.4 alkyl) aminocarbonyl; or C.sub.4 -C.sub.6
cycloalkylaminocarbonyl; L is H, F, Cl or Br; and M and R are each
independently H, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, C.sub.1
-C.sub.3 alkylthio, C.sub.1 -C.sub.3 alkylsulfinyl, C.sub.1 -C.sub.3
alkylsulfonyl, cyano, F, Cl, Br, I, nitro, CF.sub.3, R.sub.1 CF.sub.2 Z,
R.sub.2 CO or NR.sub.3 R.sub.4, and when M and R are on adjacent positions
and taken with the carbon atoms to which they are attached they may form a
ring in which MR represents the structure: --OCH.sub.2 O--, --OCF.sub.2
O-- or
##STR2##
Z is S(O)n or O; R.sub.1 is H, F, CHF.sub.2, CHFCl, or CF.sub.3 ; R.sub.2
is C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, or NR.sub.3 R.sub.4 ;
R.sub.3 is H or C.sub.1 -C.sub.3 alkyl; R.sub.4 is H, C.sub.1 -C.sub.3
alkyl, or R.sub.5 CO; R.sub.5 is H or C.sub.1 -C.sub.3 alkyl; and n is an
integer of 0, 1 or 2.
The term C.sub.4 -C.sub.6 cycloalkylamino carbonyl means a C.sub.4 to
C.sub.6 cycloalkylamino group attached directly to the carbonyl group
through the nitrogen atom.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A substituted arylpyrrole compound suitable for the present invention has
the following structure:
##STR3##
wherein x is H, F, Cl, Br, I or CF.sub.3 ; Y is H, F, Cl, Br, I, CF.sub.3
or CN; W is CN or NO.sub.2 and A is H; C.sub.1 -C.sub.4 alkyl optionally
substituted with from one to three halogen atoms, one hydroxy, one C.sub.1
-C.sub.4 alkoxy or one C.sub.1 -C.sub.4 alkylthio, one phenyl optionally
substituted with C.sub.1 -C.sub.3 alkyl or C.sub.1 -C.sub.3 alkoxy with
one to three halogen atoms, one phenoxy optionally substituted with one to
three halogen atoms or one benzyloxy optionally substituted with one
halogen substituent; C.sub.1 -C.sub.4 carbalkoxymethyl; C.sub.3 -C.sub.4
alkenyl optionally substituted with one to three halogen atoms; cyano;
C.sub.3 -C.sub.4 alkynyl optionally substituted with one halogen atom;
di-(C.sub.1 -C.sub.4 alkyl) aminocarbonyl; or C.sub.1 -C.sub.6
cycloalkylaminocarbonyl; L is H, F, Cl or Br; and M and R are each
independently H, C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, C.sub.1
-C.sub.3 alkylthio, C.sub.1 -C.sub.3 alkylsulfinyl, C.sub.1 -C.sub.3
alkylsulfonyl, cyano, F, Cl, Br, I, nitro, CF.sub.3, R.sub.1 CF.sub.2 Z,
R.sub.2 CO or NR.sub.3 R.sub.4, and when M and R are on adjacent positions
and taken with the carbon atoms to which they are attached they may form a
ring in which MR represents the structure: --OCH.sub.2 O--, --OCF.sub.2
O-- or
##STR4##
Z is S(O)n or O; R.sub.1 is H, F, CHF.sub.2, CHFCl, or CF.sub.3 ; R.sub.2
is C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, or NR.sub.3 R.sub.4 ;
R.sub.3 is H or C.sub.1 -C.sub.3 alkyl; R.sub.4 is H, C.sub.1 -C.sub.3
alkyl, or R.sub.5 CO; R.sub.5 is H or C.sub.1 -C.sub.3 alkyl; and n is an
integer of 0, 1 or 2.
In practice, the substituted arylpyrrole may be orally administered to the
animals in the form of a paste, capsule, pill, bolus, tablet, drench or
the like, containing sufficient formula I arylpyrrole to provide the
treated animal with about 0.2 mg/kg to 200 mg/kg of animal body weight and
preferably 0.5 mg/kg to 100 mg/kg of animal body weight of said
arylpyrrole.
The arylpyrrole may also be administered to the animals in or with their
feed or drinking water. In one embodiment of the invention an arylpyrrole
selected from 3-bromo-5-(P-chlorophenyl)pyrrole-2,4-dicarbonitrile;
4-bromo-2-(P-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-c
arbonitrile;
4-bromo-2-(3,4-dichlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)-pyrrol
e-3-carbonitrile; 2-(3,4-dichlorophenyl)-1-(ethoxymethyl)-5-(trifluoro;
4-5-dichloro-1-(hydroxymethyl)-2-(.alpha.,.alpha.,.alpha.-trifluoro-P-toly
l)pyrrole-3-carbonitrile acetate ester; and
3-nitro-2-phenyl-4,5-bis(trifluoromethyl)pyrrole is generally dispersed in
the feed or drinking water in sufficient amount to provide about 0.1 ppm
to 500 ppm and preferably 0.5 ppm to 100 ppm of the arylpyrrole or it may
be applied as a top dressing for the daily ration. For dispersion in the
drinking water, the pyrrole may first be dissolved in a pharmaceutically
acceptable water miscible solvent such as ethanol and then dispersed in
the water. Similarly for use in the feed the arylpyrrole may be dispersed
in a suitable solvent such as acetone and sprayed on the feed and blended
therewith or it may be prepared as an animal feed premix or concentrate
and blended with the feed prior to use.
For parenteral administration the arylpyrrole may be dispersed in a
physiologically acceptable solvent, for subcutaneous or intramuscular
injection or it may be dispersed in a fat or wax or mixture thereof
containing surfactant, preservative, stabilizer, salt, buffer and oil for
this method of treatment or for administration as an implant. Vehicle
components useful in these preparations include glyceryl dioleate, saline,
capric/caprylic triglycerides, soya oil, diethyl succinate, aluminum
monostearate gel and carbowax.
As indicated above, the arylpyrroles suitable for this invention may also
be applied topically to meat producing and companion animals to control,
prevent or treat said animals against infestation by arthropod
ectoparasites and acarids. The active compounds can be prepared as aqueous
dips for swine, cattle, sheep, horses, goats, poultry, dogs, cats and the
like or they may be prepared as wettable powders, emulsifiable
concentrates, aqueous flowables and the like, which are dispersed in water
and applied as aqueous sprays to the fur or hide of the animals. Such
sprays usually contain about 0.1 ppm to 5000 ppm and preferably 0.5 ppm to
1000 ppm of the active formula I arylpyrrole.
Advantageously, the arylpyrroles may also be prepared as pour-on
formulations and poured on the backs of the animals such as swine, cattle,
sheep, horses, goats, poultry and companion animals to protect them
against infestation by acarids and arthropod ectoparasites. Such pour-on
compositions are generally prepared by, dissolving, suspending or
emulsifying the arylpyrrole in a suitable nontoxic pharmacologically
acceptable diluent for pour-on administration. The diluent must be
compatible with the arylpyrrole and should not be a source of irritation
or damage to the animals skin or hair. Such diluents include mono and
polyhydric alcohols, vegetable oils, spreading oils, aliphatic and
aromatic hydrocarbons, lower alkyl ketones, esters and fatty acids.
A typical pour-on formulation includes about 0.5% to 30% by weight of the
substituted arylpyrrole, about 0.5 to 30% by weight of a spreading oil,
about 30% to 60% by weight of an aliphatic or aromatic hydrocarbon, mono
or polyhydric, alcohol lower alkyl ketone or mixtures thereof and 0 to
about 20% by weight of a vegetable or mineral oil. Another typical pour-on
contains about 45% by weight of xylene, about 25% by weight of
cyclohexanone, about 15% by weight of arylpyrrole, about 10% by weight of
corn oil or mineral oil and about 5% by weight of other pharmacologically
acceptable diluents such as surfactants, spreading agent, antifoam agents
or the like. Among the spreading oils that can be utilized in pour-on
formulations of this invention are fatty acids, fatty acid esters,
triglycerides and fatty alcohols including isopropyl myristate,
capryl/caproic acid esters of saturated (C.sub.12 -C.sub.18 ) fatty
alcohols with waxy fatty acid esters and isopropyl palmitate. Alcohols,
glycols and ketones useful in the present invention include ethyl alcohol,
isopropyl alcohol, propylene glycol, dipropylene glycol, benzyl alcohol,
dipropylene glycol monoethyl ether, cyclohexanone, methylethyl ketone,
methylisobutyl ketone and N-butoxybutylethoxyethanol. Vegetable oils that
may be suitable for the present invention are corn oil, olive oil, peanut
oil, sunflower oil, cottonseed oil and soybean oil. Hydrocarbons useful in
the present invention include xylene and toluene. Surfactants may also be
utilized in the formulations if desired.
A preferred group of novel arylpyrroles of the present invention are
illustrated by formula II:
##STR5##
wherein A, L, M, R, W, X and Y are as described above.
Another preferred group of novel arylpyrroles of this invention are
represented by formula III:
##STR6##
wherein A, L, M, R, W, X and Y are as described above.
Another group of preferred arylpyrroles of the invention are depicted by
formula IV:
##STR7##
wherein A, L, M, R, W, X and Y are as described above.
Yet another group of preferred arylpyrroles of this invention are
delineated by formula V:
##STR8##
wherein A, L, M, R, W, X and Y are as described above; and still other
preferred arylpyrroles of the invention as depicted by formulas VI and
VII:
##STR9##
wherein A, L, M, R, W, X and Y are described above.
Preferred formula I arylpyrroles of the invention are those in which A is
hydrogen or C.sub.1 -C.sub.4 alkoxymethyl; W is CN or NO.sub.2 ; L is
hydrogen or F; X and Y are each Cl, Br or CF.sub.3 ; M is H, F, Cl or Br;
and R is F, Cl, Br, CF.sub.3 or OCF.sub.3.
The substituted arylpyrrole compounds of the invention having the structure
of formula I, wherein A is hydrogen; W is CN and X, Y, L, M and R are as
described above, can be prepared by reacting N-formyl-DL-glycine or a
substituted N-formylphenylycine phenyl represented by the structure
formula VIII:
##STR10##
wherein L is H, F, Cl or Br; R and M are each independently H, C.sub.1
-C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.3 alkylthio,
C.sub.1 -C.sub.3 alkylsulfinyl, C.sub.1 -C.sub.3 alkylsulfonyl, cyano, F,
Cl, Br, I, nitro, CF.sub.3, R.sub.1 CF.sub.2 Z, R.sub.2 CO or NR.sub.3
R.sub.4 and when on adjacent positions and taken together with the carbon
atoms to which they are attached, M and R may form a ring in which MR
represents the structure: --OCH.sub.2 O, --OCF.sub.2 O-- or
##STR11##
Z is S(O)n or O; R.sub.1 is H, F, CHF.sub.2, CHFCl or CF.sub.3 ; R.sub.2
is C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy or NR.sub.3 R.sub.4 ;
R.sub.3 is H or C.sub.1 -C.sub.3 alkyl; R.sub.4 is H, C.sub.1 -C.sub.3
alkyl or R.sub.5 CO; R.sub.5 is H or C.sub.1 -C.sub.3 alkyl and n is an
integer of 0, 1 or 2; with at least an equivalent amount of a
2-chloroacrylonitrile and two to three equivalents of acetic anhydride.
The reaction is conducted at an elevated temperature, preferably about
70.degree. to 100.degree. C.
The reaction can be illustrated as follows:
##STR12##
Conversion of the thus prepared 2-phenylpyrrole-3-carbonitrile or
2-(substituted phenyl)pyrrole-3-carbonitrile to the corresponding formula
II, 4-halo, 5-halo or 4,5-dihalo-2-(substituted
phenyl)pyrrole-3-carbonitrile, is readily achieved by reaction of the
above said 2-phenylpyrrole-3-carbonitrile or 2-(substituted
phenyl)pyrrole-3-carbonitrile with at least about 1 or 2 equivalents of a
sulfuryl halide, bromine or chlorine, in the presence of a solvent such as
dioxane, THF, acetic acid or a chlorinated hydrocarbon solvent. For
preparation of a monohalo pyrrole-3-carbonitrile use of about 1 equivalent
of the halogenating agent is required; whereas, preparation of a dihalo
pyrrole-3-carbonitrile requires 2 to 3 equivalents of said halogenating
agent. When sulfuryl chloride or sulfuryl bromide is used the reaction is
generally conducted at a temperature below about 40.degree. C. and
preferably between about 0.degree. and 30.degree. C., but when elemental
bromine is employed, the reaction is usually conducted at about
30.degree.-40.degree. C. Other effective halogenating agents that may be
employed in these reactions include sodium hypochlorite,
t-butylhypochlorite, N-bromosuccinimide, N-iodosuccinimide and the like.
The reaction may be illustrated as follows:
##STR13##
The formula II carbonitrile compounds of the present invention may also be
prepared from the reaction of a substituted or unsubstituted benzoyl
acetonitrile with a 2,2-di(C.sub.1 -C.sub.4 alkoxy)ethylamine in the
presence of an aromatic solvent to form the .alpha.-(2,2-di-(C.sub.1
-C.sub.4 alkoxy)ethylamino)-.beta.-cyano-(substituted)styrene which is
then converted to the 2-(substituted-phenyl)pyrrole-3-carbonitrile of
formula II by reaction of said .beta.-3-cyano-(substituted)styrene
compound with trifluoroacetic acid or with concentrated HCl at a
temperature between about 20.degree. and 40.degree. C. The reactions may
be illustrated as follows:
##STR14##
wherein R.sub.6 is C.sub.1 -C.sub.4 alkyl and L, R and M are as described
above.
Also in accordance with the present invention formula II
3-nitro-2-phenylpyrrole and 3-nitro-2-(substituted)phenylpyrrole compounds
can be prepared by reaction of an .alpha.-nitroacetophenone or a
substituted .alpha.-nitroacetophenone with a 2,2-di(C.sub.1 -C.sub.4
-alkoxy)ethylamine. The reaction is generally conducted in the presence of
an inert organic solvent preferably an aromatic solvent, at an elevated
temperature to give an .alpha.-(2,2-di(C.sub.1 -C.sub.4 -
alkoxy)ethylamino)-.beta.-nitrostyrene or a substituted
.alpha.-(2,2-di(C.sub.1 -C.sub.4 -alkoxy)ethylamino)-.beta.-nitrostyrene
that is converted to the formula II 3-nitro-2-phenylpyrrole or
3-nitro-2-(substituted)phenylpyrrole by treatment with a mineral acid such
as hydrochloric or hydrobromic acid. Reaction of the thus prepared
nitrophenylpyrrole with sodium hypochlorite in the presence of an inert
organic solvent at a reduced temperature yields the formula II
2,3-dichloro-4-nitro-5-phenyl or 5-(substituted)phenylpyrrole.
The above reactions may be illustrated as follows:
##STR15##
In addition to the several methods described in the literature for
preparing substituted and unsubstituted benzoyl acetonitriles,
surprisingly we have found that these compounds may also be prepared by
reacting an appropriately substituted benzoyl halide with an alkali metal
hydride and an alkyl cyanoacetate, such as t-butyl cyanoacetate, to yield
the corresponding t-butyl(benzoyl or substituted benzoyl)cyanoacetate.
These reactions may be illustrated as follows:
##STR16##
The thus formed cyanoacetate ester can then be converted to a substituted
or unsubstituted benzoyl acetonitrile by heating the compound in toluene
containing p-toluene sulfonic acid. The reaction may be illustrated as
follows:
##STR17##
Examples of the t-butyl(benzoyl and substituted benzoyl acetonitriles)
used in the above reactions are shown in Tables below.
______________________________________
t-Butyl (benzoyl and Substituted benzoyl)cyanoacetates
##STR18##
L M R mp .degree.C.
______________________________________
H 3-Cl 4-Cl 91-94
H H 4-OCF.sub.3
81-84
H H 4-Br 113-115
H H 4-CF.sub.3 146-147
H H 4-F 98-100
H H 4-CN 127-128
H H 4-CF.sub.3 CH.sub.2 O
136-139
H H 4-CH.sub.3 SO.sub.2
127-129
H 3-F 4-F 91-94
H H 4-CH.sub.3 S
117-119.5
H H 4-CHF.sub.2 CF.sub.2 O
92-94
3-Cl 5-Cl 4-CH.sub.3 O
--
______________________________________
______________________________________
Benzoyl Acetonitriles
##STR19##
L M R mp .degree.C.
______________________________________
H H 4-Cl 128.5-129.5
H 3-Cl 4-Cl 105-107
H H 2-C 153-55
H H 4-OCF.sub.3
79-81
H H 4-CF.sub.3
44-45
H 2-Cl 4-Cl 66-67
H H 3-Cl 80-83
H H 4-CN 126-128
H H 4-F 78-80
H H 4-SO.sub.2 CH.sub.3
129-132
H 3-F 4-F 74-75
H H 3-CF.sub.3
58-60
H H 4-CH.sub.3
103.5-106
H H 4-NO.sub.2
119-124
3-Cl 5-Cl 4-OCH.sub.3
--
______________________________________
Preparation of N-substituted formula I arylpyrroles can be achieved by
reaction of the appropriately substituted formula I arylpyrrole, wherein A
is hydrogen and L, M, R, W, X and Y are as described above, with an
appropriate alkylating agent and a suitable base, for example, C.sub.1
-C.sub.4 alkylOCH.sub.2 Cl and potassium t-butoxide. This reaction
provides an arylpyrrole having the same substituents as the starting
material, but in addition is substituted on the nitrogen with C.sub.1
-C.sub.4 alkoxymethyl. In a similar reaction cyanogen bromide is
substituted for the brominated hydroxy C.sub.1 -C.sub.4 alkyl and yields
the formula I arylpyrrole with a carbonitrile substituent on the nitrogen.
The reactions may be illustrated as follows:
##STR20##
wherein L, M, R, W, X and Y are as described for formula I above and A is
1) C.sub.1 -C.sub.4 alkoxymethyl or 2) CN.
Preparation of 2-phenylpyrrole 3,4-dicarbonitrile,
2-bromo-5-phenylpyrrole-3,4-dicarbonitrile and substituted phenyl
derivatives thereof can be obtained by reaction of fumaronitrile with
bromine in the presence of a chlorinated hydrocarbon such as chloroform at
an elevated temperature to yield bromofumaronitrile. The thus formed
bromofumaronitrile is then reacted with
N-(trimethylsilyl)methyl-5-methyl-benzene-thioimidate or a substituted
derivative thereof, in the presence of hexamethylphosphoramide at an
elevated temperature to yield the 2-phenylpyrrole-3,4-dicarbonitrile.
Bromination of the thus prepared 3,4-dicarbonitrile yields the
2-bromo-5-phenylpyrrole-3,4-dicarbonitrile or the substituted phenyl
derivative if the substituted
N-(trimethylsilyl)methyl-5-methyl-benzene-thioimidate is used in the
previous reaction. The reaction may be illustrated as follows:
##STR21##
In order to facilitate a better understanding of the present invention, the
following examples are presented primarily for the purpose of illustrating
certain more specific details thereof. The invention is not to be deemed
limited thereby except as defined in the claims.
EXAMPLE 1
Evaluation of Test Compounds as Nematicidal Agents
Cultures of C. elegans (Bristol strain from J. Lewis) are maintained on E.
coli lawns on NG Agar Plates at 20.degree. C. New cultures are established
weekly.
Nematodes for testing are washed from 4-5 day old cultures using Fresh
Ascaris Ringers Solution (FARS). The worms are further washed with
FARS,-containing gentamycin, to reduce bacterial contamination and
centrifuged to separate worms from wash solution. This procedure is
repeated three times. The washed worms are then added to C. brigassae
Maintenance Medium (CbMM), from GIBCOa to which is added gentamycin (600
units/ml) and mycostatin (0.5 mg/ml).
Compounds are dissolved in acetone and made up to volume with equal parts
of water. The final test concentration of each compound in the mixture is
150 ppm. The test material is micropipetted (25 ul) into a single well of
a 96-well sterile tissue culture plate (COSTAR).sup.b and the solvent
allowed to evaporate. These "treated" plates are used immediately or
stored in a refrigerator without apparent adverse effects on the
compounds.
A freshly prepared volume (50 ug) of C. elegans in CbMM is micropipetted
into each treated well and several control wells per plate. Culture plates
are incubated at 20.degree. C.
Observations for efficacy are made under a dissecting microscope at 4 and
24 hours post-immersion. Immediately prior to reading the plate, it is
gently tapped to stimulate the movement of the worms. Activity is judged
based on the drug effects on motility of the adults and larvae. The
criteria are as follows: 9=complete kill, 8=no motility, 7=markedly
reduced motility in approximately 95% of worms, 6=reduced motility,
5=slightly reduced motility, 0=normal motility, same as controls. Other
factors indicating activity are easily noted such as death, rigor mortis,
contraction, coiling, paralysis, abnormal twitching, reduced worm
population in 48 hours and other deviation from normal behavior.
______________________________________
PROCEDURE FOR CAENORHABDITIS ELEGANS ASSAY
______________________________________
Day 0 Inoculate E. Coli-NG Agar Dish With 30-40
C. Elegans
Incubate At 20.degree. C.
Day 4 Harvest New C. Elegans Population
Wash With Antibiotics
Transfer to CbMM
Add C. Elegans (25-100 UL) To "Medicated"
Wells.sup.a
Observe for Activity at 4 hours Post-
Immersion
Day 5 Observe For Activity
______________________________________
.sup.a Medicated Wells May Be Prepared Fresh or Earlier and Stored In
Refrigerator
Data obtained in these tests are reported in Table I below.
TABLE I
______________________________________
Evaluation of Arylpyrrole Activity Against C. Elegans
Rating Against
Compound C. Elegans 150 ppm
______________________________________
2,3-Dichloro-5-(P-chloro-
9
phenyl)-4-nitropyrrole
2,5-Dichloro-3-(3,4-dichloro-
9
phenyl)-4-nitropyrrole
2,3-Dichloro-5-(3,4-dichloro-
9
phenyl)-4-nitropyrrole
2-(P-bromophenyl)-4,5-dichloro-
9
3-nitropyrrole
2,3-Dichloro-4-nitro-5-(.alpha.,.alpha.,.alpha.-
9
Trifluoro- -p-tolylpyrrole
3-Nitro-4-phenylpyrrole
9
4,5-Dibromo-2-( -0-chlorophenyl)-
9
pyrrole-3-carbonitrile
4,5-Dichloro-2-(.alpha.,.alpha.,.alpha.-
9
trifluoro- .sub.-- P-tolylpyrrole-
3-carbonitrile
4,5-Dibromo-2-(.alpha.,.alpha.,.alpha.-trifluro-
9
.sub.-- P-tolyl)pyrrole-3-carbonitrile
4,5-Dibromo-2-( .sub.-- P-nitrophenyl)-
9
pyrrole-3-carbonitrile
4,5-Dichloro-2-( .sub.-- P-nitrophenyl)-
9
pyrrole-3-carbonitrile
1-Benzyl-4,5-dibromo-2-(.alpha.,.alpha.,.alpha.-
9
trifluoro- .sub.-- P-tolyl)pyrrole-3-
carbonitrile
4,5-Dichloro-2-( .sub.-- P-cyanophenyl)-
9
pyrrole-3-carbonitrile
4,5-Dibromo-2-[ .sub.-- P-(methylsulfonyl)
9
phenyl]-pyrrole-3-carbonitrile
4,5-Dibromo-2-( .sub.-- P-cyanophenyl)-
9
pyrrole-3-carbonitrile
4,5-Dichloro-2-(3,4-dichloro-
9
phenyl)-1[2-(methylthio)ethyl]
pyrrole-3-carbonitrile
1-Alkyl-4,5-dichloro-2-(3,4-
9
dichlorophenyl)pyrrole-3-
carbonitrile
5-(3,4-Dichlorophenyl)-pyrrole-
9
3-dicarbonitrile
3-( .sub.-- P-chlorophenyl)pyrrole-
9
2-carbonitrile
4-Bromo-2-(3,4-Dichlorophenyl)-
9
5-nitropyrrole-3-carbonitrile
3,4-Dibromo-5-(3,4-dichlorophenyl)-
9
pyrrole-2-carbonitrile
2-(P-chlorophenyl)-5-nitropyrrole-
9
3-carbonitrile
4-Bromo-2-( .sub.-- P-chlorophenyl)-5-
9
(trifluoromethyl)pyrrole-3-
carbonitrile
3-Bromo-5-( .sub.-- P-chlorophenyl)pyrrole-
9
2,4-dicarbonitrile
5-(3,4-Dichlorophenyl)-4-nitro-
9
pyrrole-2-carbonitrile
3-Bromo-5-[P-(trifluoromethoxy)
9
phenyl]-pyrrole-2-4-dicarbonitrile
Bromo-5-(3,4-dichlorophenyl)-4-
9
nitropyrrole-2-carbonitrile
3,5-Dibromo-4-(P-chlorophenyl)-
9
pyrrole-2-carbonitrile
4-Bromo-2-(3,4-dichlorophenyl)-
9
5-(trifluoromethyl)pyrrole-3-
carbonitrile
4-Bromo-2-( .sub.-- P-chlorophenyl)-1-
9
(ethoxymethyl)-5-(trifluoro-
methyl)-pyrrole-3-carbonitrile
5-(.alpha.,.alpha.,.alpha.-trifluoro-tolyl)-
9
pyrrole-3-carbonitrile
4-Bromo-1-(ethoxymethyl)-5-
9
(trifluoromethyl)-2-(.alpha.,.alpha.,.alpha.-
trifluoro- .sub.-- P-tolyl)-pyrrole-
3-carbonitrile
4-Bromo-2-(3,4-dichlorophenyl)-
9
1-(ethoxymethyl)-5-(trifluoro-
methyl)-pyrrole-3-carbonitrile
2-(3,4-dichlorophenyl)-3-nitro-
9
5-trifluoromethyl)pyrrole
4-Bromo-5-nitro-2-(.alpha.,.alpha.,.alpha.-
9
trifluoro- .sub.-- P-tolyl)pyrrole-
3-carbonitrile
2,4-Dibromo-5-(.alpha.,.alpha.,.alpha.-trifluoro-
9
P-tolyl)pyrrole-3-carbonitrile
4-Bromo-2-(2,4-dichlorophenyl)-
9
5-(trifluoromethyl)pyrrole-3-
carbonitrile
4,5-Dichloro-1-(1-ethoxymethyl)-
9
2-(.alpha.,.alpha.,.alpha.-trifluoro-P-tolyl)-
pyrrole-3-carbonitrile
4,5-Dichloro-2-(3,4-dichloro-
9
phenyl)-1-[2-(dimethylamino)
ethyl]pyrrole-3-carbonitrile
4-Bromo-2-(2,4-Dichlorophenyl)-
9
1-(ethoxymethyl)-5-(trifluoro-
methyl)pyrrole-3-carbonitrile
1-Benzyl-3-bromo-5-( .sub.-- P-chloro-
9
phenyl)pyrrole-2,4-dicarbo-
nitrile
4-Bromo-2-(m-nitrophenyl)-5-
9
(trifluoromethyl)pyrrole-3-
carbonitrile
5-Bromo-3-( .sub.-- P-chlorophenyl)-
9
pyrrole-2,4-dicarbonitrile
3-( .sub.-- P-chlorophenyl)-4-nitro-
9
pyrrole
3-Bromo-5-( .sub.-- P-chlorophenyl)-
9
4-cyano-2-(trifluoromethyl)-
pyrrole-1-acetonitrile
4-Bromo-2-( .sub.-- P-chlorophenyl)-1-
9
(1-methoxymethyl)-5-(trifluoro-
methyl)pyrrole-3-carbonitrile
4,5-Dichloro-1-(hydromethyl)-2-
9
(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-tolyl)
2,3,-Dichloro-4-cyano-5-(.alpha.,.alpha.,.alpha.-
9
trifluoro- .sub.-- P-tolyl)pyrrole-1-
acetonitrile
4,5-Dichloro-1-(methoxyethyl)-2-
9
(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-tolyl)pyrrole-
3-carbonitrile
3-Nitro-2-phenyl-4,5-bis(trifluoro-
9
methyl)pyrrole
4-Bromo-3-( .sub.-- P-chlorophenyl-
9
5-(trifluoromethyl)pyrrole-
3-carbonitrile
4-Phenyl-5-(trifluoromethyl)
9
pyrrole-3-carbonitrile
2-Bromo-4-phenyl-5-(trifluoro-
9
methyl)pyrrole-3-carbonitrile
2-Bromo-4-( .sub.-- P-chlorophenyl)-5-
9
(trifluoromethyl)pyrrole-3-
carbonitrile
2-( .sub.-- P-bromophenyl)-3,5-
9
dimitropyrrole
2-( .sub.-- P-chlorophenyl)-4,5-bis
9
(trifluoromethyl)pyrrole-3-
carbonitrile
3-( .sub.-- P-chlorophenyl)-2-(tri-
9
fluoromethyl)pyrrole
______________________________________
EXAMPLE 2
Evaluation of Arylpyrroles Against Psoroptes cuniculi
On the day prior to the test initiation the drugs to be evaluated are
dissolved in acetone and diluted to the desired concentrations. The
concentration is calculated so that 400 .mu.l contains the amount of test
compound to be placed on each filter paper. 400 .mu.l of this solution is
pipetted onto a top (3.7 cm dia.) and bottom (3.5 cm dia.) filter paper
disks which are then placed on a ceramic plate to dry. There is a rough
and smooth side to the filter paper. Drug should be applied to the rough
side which is placed up while drying. When dry the two disks are placed in
a Petri dish with the rough sides facing in, separated by one 3 mm glass
bead. Dishes are held at room temperature overnight if done the day before
the test.
Scab (containing mites) is collected from the ears of infested rabbits the
morning of the test. This material is placed in a large Petri dish under
an illuminated magnifier. Mites crawl out of the scab and are easily
collected on the point of a dissecting needle or one prong of a pair of
fine forceps. The top filter paper in each dish is removed and 12 mites
are placed on the bottom disk and the top paper replaced. Before replacing
the top of the Petri dish the rim of the dish is smeared with Vaseline to
trap any escaping mites.
For evaluation tests there are generally 4 replicates of each dose which
are counted at 24 hours. After mites are added to the dishes, the dishes
in each replicate are placed in a tray which is then placed in a plastic
bag with several wet towels and held at room temperature.
After 24 hours dishes are examined under a dissecting scope. Each dish is
opened carefully and the top filter paper removed and saved. A 1/2 cm
circle is drawn on the bottom filter paper and the paper gently wet in the
area of the circle. All mites from the dish are transferred into the wet
circle area and counted. The top cover is replaced on each dish and the
dishes set aside for at least 15 minutes. After standing the dishes are
examined and the mites remaining on the circle counted. These mites are
dead. Percent mortality of the mites is then calculated for each
treatment. These data are reported in Table II below.
TABLE II
______________________________________
Evaluation of arylpyrroles against Psoroptes
cuniculi (Rabbit Ear Mite)
24 hour
Compound .mu.g/cm.sup.2
% Mortality
______________________________________
2,3-Dichloro-5-( .sub.-- P-chloro-
10.0 91
phenyl)-4-nitropyrrole
4.0 52
3-Bromo-5-( .sub.-- P-chloro-
4.0 48
phenyl)pyrrole-2,4-
dicarbonitrile
2,4-Dibromo-5-( .sub.-- P-chloro-
4.0 11
phenyl)pyrrole-3-carbo-
nitrile
2-(2,4-Dichloro-5-fluoro-
4.0 73
phenyl)pyrrole-3-carbo-
nitrile
4,5-Dichloro-2-(3,4-
10.0 33
dichlorophenyl)pyrrole-
3-carbonitrile
2-(3,4-Dichlorophenyl)-3-
4.0 100
nitro-(trifluoromethyl)-
pyrrole
4-Bromo-2-( .sub.-- P-chloro-
4.0 76
phenyl)-1-(ethoxymethyl)-5-
(trifluoromethyl)pyrrole-3-
carbonitrile
4-Bromo-2-( .sub.-- P-bromophenyl)-
4.0 31
1-(ethoxymethyl)-5-(tri-
fluoromethyl)pyrrole-3-
carbonitrile
4,5-Dichloro-1-(ethoxy-
16.0 100
methyl)-2-(.alpha.,.alpha.,.alpha.-trifluoro-
4.0 92
.sub.-- P-tolyl)pyrrole-3-carbo-
1.0 100
nitrile 0.1 20
0.01 48
4,5-Dichloro-1-(ethoxy-
4.0 100
methyl)-2-[P-(trifluoro-
methoxy)phenyl]pyrrole-
3-carbonitrile
2-(3,4-Dichlorophenyl)-1-
4.0 92
(ethoxymethyl)-3-nitro-
5-(trifluoromethyl)pyrrole
2,3-Dichloro-4-cyano-5-
4.0 77
(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-tolyl)-
pyrrole-1-acetonitrile
______________________________________
EXAMPLE 3
Evaluation of Arylpyrroles against the Larval Stages of the Dogtick,
Dermacentor variabilis
The test procedure used herein is the same procedure described in Example
2, for evaluating the arylpyrroles for control of Psoroptes cuniculi the
Rabbit Ear Mite, with the following exceptions:
(1) Unfed larval ticks are obtained from egg masses laid by gravid female
ticks removed from dogs and each replicate receives ticks from the same
egg mass;
(2) Ticks survive longer than mites in the Petri dishes, thus readings are
made 48 hours or longer after the test is initiated; and
(3) When reading the test it may be necessary to blow on the ticks to
stimulate their movement.
Data obtained are reported in Table III below.
TABLE III
______________________________________
Evaluation of Arylpyrroles against the larval stages
of the Dogtick, Dermacentor variabilis
% mortality
Compound .mu.g/cm.sup.2
@ 48 hour
______________________________________
2,3-Dichloro-5-( .sub.-- P-chloro-
10.0 58
phenyl)-4-nitropyrrole
4,5-Dichloro-2-(3,4-dichloro-
10.0 40
phenyl)pyrrole-3-carbonitrile
4-Bromo-2-( .sub.-- P-chlorophenyl)-1-
10.0 100
(ethoxymethyl)-5-(trifluoro-
5.0 100
methyl)pyrrole-3-carbonitrile
4.0 83
1.0 77
4,5-Dichloro-1-(ethoxymethyl)-
10.0 97
2-(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-tolyl)-
5.0 100
pyrrole-3-carbonitrile
1.0 52
4,5-Dichloro-1-methyl-2-
10.0 55
[P-(trifluoromethoxy)phenyl]-
pyrrole-3-carbonitrile
______________________________________
EXAMPLE 4
Evaluation of Arylpyrrole Compounds against Ctenocephalides felis the Cat
Flea
This test is conducted in the same manner as the mite filter paper test
described in Example 2 with the following exceptions:
(1) only one filter paper is used on the bottom of the dish;
(2) Unfed fleas that have emerged from pupae within the last 24 hours are
used for the test. Fleas are initially collected in glass vials and then
temporarily immobilized by placing the vials in ice. Once the fleas are no
longer active, vials are opened and fleas dumped into Petri dishes. The
number of fleas per dish will vary but generally contain 8-12 fleas.
(3) Dishes are held for 24 hours until the mortality counts are made;
(4) Edges of the Petri dish are sealed with Scotch tape to prevent escape
of the fleas; and
(5) Dishes are not opened when test is read but fleas are observed under
dissecting scope in the dishes. Some fleas will move under the filter
paper so dish should be inverted to check. Fleas are considered dead if
they cannot remain upright and jump.
Data obtained are reported in Table IV below.
TABLE IV
______________________________________
Evaluation of Arylpyrrole Compounds against
Ctenocephalides felis the cat flea
24 hour
Compound .mu.g/cm.sup.2
% Mortality
______________________________________
3-Bromo-5-( .sub.-- P-chlorophenyl)-
20.0 47
pyrrole-2,4-dicarbonitrile
2-(3,4-Dichlorophenyl)-3-
20.0 73
nitro-5-(trifluoromethyl)-
pyrrole
4,5-Dichloro-1-(ethoxy-
20.0 71
methyl)-2-(.alpha.,.alpha.,.alpha.-trifluoro-
.sub.-- P-tolyl)pyrrole-3-
carbonitrile
______________________________________
EXAMPLE 5
Evaluation of Arylpyrrole Compounds against Newly Emerged Housefly Larvae
In this test system newly emerged housefly larvae are grown on an undefined
medium of fermented whole milk and dried beef blood. Compounds are added
to the milk and activity is determined by the failure of larvae to pupate.
The test is run in 1 oz. plastic medicine cups. Paper toweling is cut in
pieces approximately 3.5.times.10 cm. Three of these pieces are folded
accordion style and placed in each paper cup. A piece of masking tape is
placed on the outside of the cup to facilitate numbering. Cups should be
prepared prior to the day the test is to begin.
Newly hatched housefly larvae are obtained on the morning the test is to
begin. The eggs are laid the night before and larvae usually begin to
hatch by 9-10 AM the following morning.
Twenty-four hours before the initiation of the test, one half gallon of
whole milk is divided into 5 1-liter beakers and placed in an incubator at
39.degree. C.
The morning of the test, one 250 ml beaker is labeled for each treatment.
The fermented milk is removed from the incubator, stirred and poured into
each of the small beakers. The beakers are then returned to the incubator
and 1-2 g of dried beef blood added to each beaker to distribute blood
which will not dissolve. The beakers are again returned to the incubator.
Doses of compounds are calculated so that 0.1 ml contains the amount of
compound to be added to 100 ml of milk. Compounds should be dissolved in
acetone. 100 .mu.l of acetone is added to each control beaker.
Each beaker is removed from incubator and placed on a magnetic stirrer. The
compound is added and thoroughly mixed. Then 20 ml portions are removed
and added to labelled test cups (4 reps/treatment). Cups are placed in
stainless steel tray until all are prepared. Once prepared cups are held
for 24 hours if fly eggs do not hatch on time. The tray containing the
cups are then placed in a plastic bag and maintained at room temperature.
The media that the fly eggs are laid in is spread out in a green or black
pan so that larvae can be observed. Working under an illuminated magnifier
20 larvae are transferred into each cup using a fine paint brush. Each cup
is then sealed in a Zip-Loc sandwich bag with a few pinholes in it.
Bags containing cups are placed on a flat tray and placed in a 27.degree.
C. incubator for one week. The majority of the larvae will have pupated at
this point.
Trays are then removed from the incubator and the number of pupae in each
bag recorded. The paper toweling is removed and examined closely for any
pupae that have remained in the cups. Most of the pupae will be loose in
the bag. A note is also made of any dead or live developed larvae. If
there are larvae that appear capable of pupating, the bag may be returned
to the incubator for a day to see if they will pupate.
The percent development of pupae is then calculated. The final results are
expressed as a percent inhibition of pupation and are corrected for
control mortality by using Abbott's formula. Data obtained are reported
below in Table V.
TABLE V
______________________________________
Evaluation of arylpyrrole compounds against newly
hatched Housefly Larvae
Conc % Inhibition
Compound ppm of pupation
______________________________________
3-Bromo-5-( .sub.-- P-chlorophenyl)-
10.0 100
pyrrole-2,4-dicarbonitrile
1.0 0
2-(3,4-Dichlorophenyl)-3-
10.0 100
nitro-5-(trifluoromethyl)-
pyrrole
4-Bromo-2-( .sub.-- P-chlorophenyl)-
10.0 99
1-(ethoxymethyl)-5-(tri-
5.0 38
fluoromethyl)pyrrole-3-
2.5 0
carbonitrile 1.0 15
4,5-Dichloro-1-(ethoxymethyl)-
10.0 64
2-(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-tolyl)-
pyrrole-3-carbonitrile
2,3-Dichloro-4-cyano-5-
10.0 100
(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-tolyl)-
pyrrole-1-acetonitrile
______________________________________
EXAMPLE 6
Evaluation of Arylpyrroles for Control of Helminths in Warm-blooded Animals
Each test generally consists of 75 infected gerbils, randomly distributed 2
or 3 per cage (the number of animals per cage is consistent within a
specific experiment). Generally, there are 8-9 untreated control gerbils
(3-4 cages) per test. The remaining cages are assigned a treatment,
usually 1 cage per compound or dose.
Compounds administered in diet are fed for 4 days. Animals treated by
gavage or injection are generally treated on only 1 day (usually day 7).
In accordance with this test, gerbils are each orally infected by gavage,
with about 400 Trichostrongylus colubriformis infective larvae of sheep
origin. The infected animals are then permitted to feed and drink ad
libitum for six days. On day 7 the infected gerbils are randomly placed in
rodent cages 2 or 3 animals per cage. The animals in each cage are weighed
and the feed for each cage weighed. If the treatment to be evaluated is
medicated feed, said medicated feed is offered on day 7 and continued
through day 11 of the trial. If the treatment to be evaluated is a single
oral dose or a parenteral treatment, the animals are given the medication
by gavage or injection on day 7 and receive unmedicated feed and water
through day 11 of the trial. On day 11 the animals and their feed are
weighed. Thereafter the animals are euthanized by CO.sub.2 inhalation and
their small intestines removed, inverted on application sticks and
incubated in tap water at 39.degree. C. for 1-5 hours. The sticks and
intestines are then discarded and the worms from each treatment counted to
determine the % mortality of the worms as compared to untreated controls.
Data obtained are reported in Table VI below.
TABLE VI
______________________________________
Evaluation of Formula I arylpyrrole compounds
against T. colubriformis in Gerbils
______________________________________
PPM in % Helminth
Compound Diet removal
______________________________________
3-Bromo-5-( .sub.-- P-chlorophenyl)-
500 54
pyrrole-2,4-dicarbonitrile
500 36
500 50
Single oral dose
25 mg/kg 18
10 mg/kg 25
4-Bromo-2-( .sub.-- P-chlorophenyl)-
500 29
1-(ethoxymethyl)-5-(trifluoro-
methyl)-2-(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-
tolyl)pyrrole-3-carbonitrile
4-Bromo-1-(ethoxymethyl)-
500 13
5-(trifluoromethyl)pyrrole-
3-carbonitrile
4-Bromo-2-(3,4-dichlorophenyl)-
500 15
1-(ethoxymethyl)-5-(trifluoro-
methyl)pyrrole-3-carbonitrile
4-Bromo-2-(3,4-dichloro-
500 28
phenyl)-1-(ethoxymethyl)-5-
(trifluoromethyl)pyrrole-3-
carbonitrile
4,5-Dichloro-1-(hydroxy-
500 37
methyl)-2-(.alpha.,.alpha.,.alpha.-trifluoro- .sub.-- P-
500 8
tolyl)-3-carbonitrile
acetate ester
3-Nitro-2-phenyl-4,5-
500 42
bis(trifluoromethyl)pyrrole
______________________________________
EXAMPLE 7
Preparation of 2-Phenylpyrrole-3-carbonitrile
##STR22##
The following procedure is similar to the method given in JOC, 43, 4273-6
(1978). A stirred mixture of 30.0 g of N-formyl-phenylglycine is heated at
90.degree. C. for 1.5 hours. The clear yellow reaction solution is
concentrated in vacuo to give 42.5 g of an oily brownish orange
semi-solid. Material partially purified by chromatography on silica gel is
shown by the proton NMR spectrum to be a mixture of 73%
2-phenylpyrrole-3-carbonitrile and 27% 2-phenyl-3-cyano-5-methylpyrrole.
Recrystallization once from chloroform and twice from 1,2-dichloroethane
gives 1.69 g of an off-white solid which proton NMR shows it to be 96%
2-phenylpyrrole-3-carbonitrile, mp 148.degree.-152.degree. C.
EXAMPLE 8
Preparation of 4,5-Dichloro-2-phenylpyrrole-3-carbonitrile and
5-chloro-2-phenylpyrrole-3-carbonitrile
##STR23##
To a stirred ice-water cooled solution of 2.00 g (11.9 mmol,) of
2-phenyl-3-cyanopyrrole in 80 mL of methylene chloride is added dropwise
over a period of 5 min., 1.90 mL (3.19 g, 23.6 mmol,) of sulfuryl chloride
by means of a syringe. Throughout the addition the temperature is kept
between 5.degree. C. and 10.degree. C. Stirring at 5.degree.-10.degree. C.
is continued for 90 minutes. The reaction mixture is vacuum filtered to
remove a precipitated solid (1.28 g) identified as
5-chloro-2-phenylpyrrole-3-carbonitrile, mp 192.5.degree.-195.degree. C.
The filtrate is diluted with 400 mL of ethyl acetate, washed twice with
200 mL of water, dried (sodium sulfate), treated with charcoal, filtered,
and then concentrated in vacuo to give (after slurrying of the residue
with hexane) 0.60 g (21.3% yield) of a pink-purple solid. This solid is
recrystallized from 5 mL of hot acetone to give 0.32 g (9% yield) of
4,5-dichloro-2-phenylpyrrole-3-carbonitrile as an orangish brown solid, mp
254.degree.-255.degree. C.
EXAMPLE 9
Preparation of p-Chloro-.beta.-[(formylmethyl)amino]cinnamonitrile, diethyl
acetal
A stirred solution of 250.00 g (1.39 mol,) of p-chlorobenzoylacetonitrile,
203 mL (185.95 g, 1.39 mol) of 2,2-diethoxyethylamine, and 1300 mL of
dried toluene is heated at reflux for 20 hours. Water is collected in a
Dean-Stark trap (23.8 mL, 95.2% theory). The hot cloudy dark brown
solution with a large amount of undissolved solids is filtered through
diatomaceous filter aid. After dilution with 200 mL of EtoAc, the solution
is filtered through a 7 cm.times.13.5 cm column of silica gel. The
filtrate is concentrated in vacuo to give 354.38 g (86.4% crude yield) of
a clear dark oil which slowly solidifies. This solid is recrystallized
from hot cyclohexane to give 324.26 g (79.1% yield) of a waxy orange
solid. NMR of this product shows it to be composed of 78% (Z) and 23% (E)
isomeric mixture of p-chloro-.beta.-[(formylmethyl)amino]cinnamonitrile,
diethyl acetal, mp 60.degree.-72.degree. C.
EXAMPLE 10
Preparation of 2(p-Chlorophenyl)-pyrrole-3-carbonitrile
##STR24##
To 108 mL of trifluoroacetic acid stirred at 23.degree. C. is added 54.00 g
(0.183 mol) of solid p-chloro-.beta.-[(formylmethyl)amino]cinnamonitrile,
diethyl acetal over a period of 45 minutes. This addition produced an
exotherm to 38.degree. C. and, 32 minutes into the addition, a solid
started to precipitate. After stirring at room temperature for 30 minutes,
the reaction mixture is vacuum filtered and the collected solid is washed
first with trifluoroacetic acid, secondly with an ethyl acetate-hexane
mixture, and finally with hexane. The yield is 16.83 g (45.4%) of an
off-white solid, mp 165.degree.-166.degree. C.
Use of the above procedure as shown or with the substitution of
concentrated hydrochloric acid for trifluoroacetic acid affords the
following compounds:
______________________________________
##STR25##
M and/or R mp .degree.C.
Acid Used
______________________________________
4-Cl 165-166 conc. HCl,CF.sub.3 COOH
3,4-di-Cl 216-221 CF.sub.3 COOH
2-Cl 156-157 CF.sub.3 COOH
4-OCF.sub.3 143-145 CF.sub.3 COOH
4-CF.sub.3 179-180 CF.sub.3 COOH
2,4-di-Cl 197-199 CF.sub.3 COOH
3-Cl 150-156 CF.sub.3 COOH
4-CN 210-212 CF.sub.3 COOH
4-F 167-170 conc. HCl
4-SO.sub.2 CH.sub.3
221-221.5
CF.sub.3 COOH
3,4-di-F 173-175.5
CF.sub.3 COOH
3-CF.sub.3 166-168 CF.sub.3 COOH
4-COOCH.sub.3
155.5-158
CF.sub.3 COOH
4-CH.sub.3 117-137 CF.sub.3 COOH
4-NO.sub.2 174-177 CF.sub.3 COOH
______________________________________
EXAMPLE 11
Preparation of 4,5-Dichloro-2-(p-chlorophenyl)pyrrole-3-carbonitrile
##STR26##
To a stirred solution of 16.83 g (83.1 mmol) of
2-(p-chlorophenyl)pyrrole-3-carbonitrile in 450 mL of glacial acetic acid
at 36.degree. C. is added dropwise 14.7 mL (24.70 g, 183.0 mmol) of
sulfuryl chloride over a period of 18 minutes. The addition produces a
slight exotherm to 39.degree. C. and, after another 16 minutes, the
reaction mixture is vacuum filtered. The collected solids are washed first
with acetic acid and then with water. This solid after recrystallization
from hot ethyl acetate, melts at 259.degree.-261.degree. C.
EXAMPLE 12
Preparation of
4,5-Dibromo-2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyrrole-3-carboni
trile
##STR27##
To a stirred mixture of 0.8 g of
2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyrrole-3-carbonitrile in 70
mL of chloroform is added 2 mL of bromine. The mixture, on stirring
overnight, deposits a white solid which is collected by filtration. Thin
layer chromatography (1:1 ethyl acetate-hexane) shows a single component;
mp >230.degree. C.
Following the procedures of Examples 11 and 12, but substituting the
appropriately substituted phenyl-pyrrole-3-carbonitrile for
2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyrrole-3-carbonitrile yields
the following compounds.
______________________________________
##STR28##
L M R X Y mp .degree.C.
______________________________________
H H 4-NO.sub.2
Br Br 274-277
H H 4-F Cl Cl >220
H H 4-F Br Br >220
H H 4-SO.sub.2 CH.sub.3
Cl Cl >230
H 3-F 4-F Cl Cl >230
H 3-F 4-F Br Br >220
2-Cl 3-Cl 4-Cl Cl Cl
2-Br 3-Br 4-Br Br Br
H H 4-OCF.sub.3
Cl Cl 222-225
H H 4-OCF.sub.3
Br Br 231-232
H H 4-OCF.sub.3
Cl H
H H 4-CN Br Br >230
H H 4-CN Cl Cl >240
H H 4-SO.sub.2 CH.sub.3
Br Br >230
H H 4-NO.sub.2
Cl Cl 246-249
H 3-Cl 4-Cl Br Br >260
H H 3-CF.sub.3
Cl Cl >230
H H 4-COCH.sub.3
Cl Cl 251-254
H 2,3-CHCH Cl Cl 244-247
H H 4-CH.sub.3
Cl Cl 215-217
H 2-Cl 4-Cl Br Br >230
H H 3-Cl Cl Cl >230
H 2-Cl 4-Cl Cl Cl >230
H H 4-Cl Br Br 273-274
H H 2-Cl Br Br >230
H H 4-CF.sub.3
Cl Cl >230
H H 4-Br Cl Cl >235
H H 2-Cl Cl Cl >230
H 3-Cl 4-Cl Cl Cl >235
H H H Cl Cl 254-255
H H 4-Cl Cl Cl 255-257
H H 4-CF.sub.3
Br Br >230
H H 4-Cl Cl Br 262-263
(dec.)
H H 4-Cl Br Cl 250-258
(dec.)
H 3-Cl 5-Cl Cl Cl >230
H 3-Cl 4-Cl Cl Br >230
2-Cl 4-Cl 5-F Cl Cl 207-210
______________________________________
EXAMPLE 13
Preparation of 3-Nitro-2-phenylpyrrole
Alpha-nitro acetophenone (5.7 g, 0.0345 mol) is taken up in 100 mL toluene
and 4.6 g (0.0345 mol) of amino acetaldehyde diethyl acetal is added. The
reactants are put into a 250 mL RB flask fitted with a Dean-Stark trap.
The trap is filled with 4A molecular sieves and the mixture is heated at
reflux for 18 hours. The toluene is removed in vacuo to give 8.36 g of
.alpha.-(2,2-diethoxyethylamino)-.beta.-nitrostyrene as a brown oil. To
this oil is added 50 mL of concentrated HCl. As the flask is swirled the
oil turns to a yellow suspension. After 10 minutes the solid is filtered
to give 2.48 g of a yellow solid. Recrystallization from
ether/ethylacetate/hexane gives the product as two fractions, 2.08 g of mp
190.degree.-192.degree. C.
EXAMPLE 14
Preparation of 2,3-Dichloro-4-nitro-5-phenylpyrrole
##STR29##
A mixture of 3-nitro-2-phenylpyrrole (1.56 g, 0.0083 mol) in 60 mL of
dioxane is cooled in an ice bath while 25.9 g (0.0182 mol) of commercial
sodium hypochlorite is added dropwise. After stirring for 45 minutes, the
mixture is acidified with concentrated HCl. Water and Et.sub.2 O are
added. The layers are separated and the top organic layer is washed with
H.sub.2 O, dried over anhydrous MgSO.sub.4 and concentrated in vacuo to
give 2.21 g of yellow solid. Purification by chromatography using silica
gel and eluting with increasing ratios of ethyl acetate/ hexane gives,
after stripping, 0.77 g of yellow solid (36%) mp 190.degree.-190.5.degree.
C.
Following the procedures of Examples 13 and 14 above but using the
appropriately substituted .alpha.-nitro-acetophenone and 2,2-di(C.sub.1
-C.sub.4 alkoxy)ethylamine yields the substituted .alpha.-(2,2-di(C.sub.1
-C.sub.4 alkoxy)ethylamino-.beta.-nitrostyrene which is then converted to
3-nitro-2-(substituted)phenylpyrrole by treatment with HCl, HBr or
CF.sub.3 CO.sub.2 H. Reaction of the thus formed substituted phenylpyrrole
with sodium hypochlorite in dioxane yields the chloro analogs; whereas,
reaction of the substituted phenylpyrrole with bromine in chloroform
yields the bromine analogs.
______________________________________
##STR30##
L M R X Y mp .degree.C.
______________________________________
H H H Cl Cl 190-190.5
H 4-Cl H Cl Cl 214-215
H 4-Cl H Br Br 203-204
(dec.)
H H H Br Br 148.5-149
3-Cl 4-Cl C Cl Cl 219-220
(dec.)
H 4-Br H Cl Cl 222-223
(dec.)
H H 4-CF.sub.3
Cl Cl 166-168
______________________________________
EXAMPLE 15
Preparation of
4,5-Dichloro-2-(3,4-dichlorophenyl)-1-methyl-pyrrole-3-carbonitrile
##STR31##
In a 100 mL flask, 2 g of
4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile in 60 mL dry THF
gives a clear brown solution. 1 equivalent of KOtBu is added with
stirring, this giving a clear solution after a few minutes. 1 equivalent
of MeI is added by syringe and the solution is heated at reflux for 4
hours. It is then left to stir at room temperature overnight. The
following day 50 mL of H.sub.2 O is added and the mixture extracted with
4.times.50 mL CHCl.sub.3. The organic phases are combined, dried with
MgSO.sub.4, and concentrated. The resulting white solid is purified by
flash chromatography on silica gel, using 50/50 EtOAc/hexane as an
eluent. This gives 1.80 g of a white solid, mp 154.degree.-156.degree. C.
Following the above procedure but substituting the appropriately
substituted phenylpyrrole-3-carbonitrile or
3-nitro-2-(substituted)phenylpyrrole for
4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile yields the
compounds shown below.
______________________________________
##STR32##
A L M R X Y mp .degree.C.
______________________________________
CH.sub.3 H H 4-Cl Cl Cl 152-153
C.sub.2 H.sub.5 OCH.sub.2
H 3-Cl 4-Cl Cl Cl 128-130
C.sub.2 H.sub.5
H 3-Cl 4-Cl Cl Cl 137-138
CH.sub.3 H 3-Cl 4-Cl Cl Cl 154-156
CH.sub.3 H H 4-CF.sub.3
Br Br 145-146
C.sub.6 H.sub.5CH.sub.2
H H 4-CF.sub.3
Br Br 145-147
C.sub.6 H.sub.5CH.sub.2
H 3-Cl 4-Cl Cl Cl 95-96
CH.sub.2CHCH.sub.2
H 3-Cl 4-Cl Cl Cl 69-70
CH.sub.2CCH.sub.2
H 3-Cl 4-Cl Cl Cl
Cl
CHCCH.sub.2
H 3-Cl 4-Cl Cl Cl 147-148
CH.sub.3 SCH.sub.2
H 3-Cl 4-Cl Cl Cl
C(CH.sub.3).sub.3
H H 4-CF.sub.3
Cl Cl
CH.sub.3 H H 4-CF.sub.3
Cl Cl 99-100
CH.sub.3 SC.sub.2 H.sub.5
H 3-Cl 4-Cl Cl Cl 74-75
C.sub.2 H.sub.5OCCH.sub.2
H 3-Cl 4-Cl Cl Cl 118-120
C.sub.2 H.sub.5OCH.sub.2
H H 4-CF.sub.3
Cl Cl 99-100
CH.sub.3 H H 4-OCH.sub.3
Br Br 112-115
CH.sub.3 H H 4-Cl Br Br 197-201
C.sub.2 H.sub.5 OCH.sub.2
H H 4-OCF.sub.3
Cl Cl 46-47
CH.sub.3 H H 4-OCF.sub.3
Cl Cl 72-73
C.sub.6 H.sub.5CH.sub.2
H H 4-OCF.sub.3
Cl Cl oil
C.sub.2 H.sub.5 OCH.sub.2
H H 4-Cl Cl Cl --
HOCH.sub.2 CH.sub.2
H 3-Cl 4-Cl Cl Cl 143-145
NC H 3-Cl 4-Cl Cl Cl 251-252
C.sub.6 H.sub.5 CH.sub.2 OCH.sub.2
H 3-Cl 4-Cl Cl Cl 88-89
Cl OCH.sub.2
H 3-Cl 4-Cl Cl Cl 118-120
ICCCH.sub.2
H 3-Cl 4-Cl Cl Cl 115-116
CH.sub.3 H H 4-Cl Br CF.sub.3
126-129
C.sub.2 H.sub.5 OCH.sub.2
H H 4-Cl Br CF.sub.3
91- 92
C.sub.2 H.sub.5OCH.sub.2
H 3-Cl 4-Cl Cl Cl 118-120
C.sub.2 H.sub.5OCH.sub.2
H H 4-Cl Br Br 104-105
C.sub.6 H.sub.5CH.sub.2
H H 4-Cl Br Br 81-82
CH.sub.3 H H 4-Cl Br Br 197-201
CN H H 4-CF.sub.3
Cl Cl 138-139
C.sub.2 H.sub.5OCH.sub.2
H H 4-CF.sub.3
Br CF.sub.3
104-105
C.sub.2 H.sub.5OCH.sub.2
H H 4-CF.sub.3
H CF.sub.3
76-77
C.sub.2 H.sub.5 OCH.sub.2
H 3-Cl 4-Cl Br CF.sub.3
80-81
______________________________________
EXAMPLE 16
Preparation of
1-Benzyl-4,5-dibromo-2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyrrole-
3-carbonitrile
##STR33##
In a 100 mL flask, 1.5 g of
4,5-dibromo-2-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyrrole-3-carboni
trile is mixed with 50 mL dry THF to give a clear dark solution. 1 eq of
KOtBu is added with stirring. After a few minutes the solution clears.
Benzyl bromide (0.65 g) is added by syringe. The mixture is heated at
reflux overnight. The following day TLC (50/50 EtOAc/hexane) indicates the
presence of both starting material and product. The reaction is worked up
in the following manner; 50 mL of water is added and the mixture is
extracted with 4.times.50 mL CHCl.sub.3. The organic phases are combined
and washed with 4.times.50 mL 10% aq. NAOH. The organic phase is dried
with MgSO.sub.4 and stripped. This gives a brown solid which is
crystallized from EtOAc/hexane, mp 145.degree.-147.degree. C.
EXAMPLE 17
Preparation of
4,5-Dichloro-2-(3,4-dichlorophenyl)-1-(ethoxymethyl)-pyrrole-3-carbonitril
##STR34##
A sample of 4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (1.0
g, 0.003 mole) is dissolved in 10 mL of dry tetrahydrofuran. To this
solution is added potassium t-butoxide (0.37 g, 0.0033 mole) followed by
chloromethyl ethyl ether (0.312 g, 0.0033 mole). The mixture is stirred
for about 1 hour at room temperature and then poured into a large volume
of water precipitating the product. The white solid is collected and dried
to give 1.0 g (91%) with mp 128.degree.-130.degree..
EXAMPLE 18
Preparation of 5-bromo-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile
##STR35##
A sample of 2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (2.0 g, 0.008
mole) is dissolved in 100 mL of dioxane by warming to
40.degree.-50.degree.. Then the solution is cooled to 30.degree. C. and
bromine (1.3 g, 0.008 mole) is added. After stirring 1 hour at room
temperature the solution is poured into water and a gray solid (2.2 g,
88%) is collected. The mp is 233.degree.-236.degree. C., decomposition.
In a similiar fashion one can prepare
5-bromo-2-(3,4-dichloro)-3-nitropyrrole starting with
2-(3,4-dichlorophenyl)-3-nitropyrrole.
EXAMPLE 19
Preparation of 5-(p-chlorophenyl)pyrrole-2,4-dicarbonitrile
##STR36##
A sample of 2-p-chlorophenyl-3-cyanopyrrole, prepared by the method of
Example 4, (3.0 g, 0.015 mole) is dissolved in 50 mL of dry
dimethoxyethane. To this solution is added chlorosulfonyl isocyanate (3.39
g, 0.024 mole). The addition is exothermic and some cooling is necessary.
After stirring 3 hours at room temperature, dimethylformamide (6-7 mL) is
added and the solution is stirred 4 hours more. The solution is then
poured into water precipitating a white solid (3.4 g, 100%). A sample (1.0
g) is purified by dissolving in ethyl acetate and then passing the
solution through a 60 mL course filter funnel packed with silica gel. The
filtrate is concentrated to yield 0.7 g of a white solid with mp
235.degree.-240.degree. C.
Following the procedure of Example 19, the following analogs are prepared:
______________________________________
##STR37##
R L mp
______________________________________
3-Cl 4-Cl >225.degree. C.
H 4-OCF.sub.3
185-190.degree. C.
H 4-CF.sub.3
180-185.degree. C.
______________________________________
EXAMPLE 20
Preparation of 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile
4-(p-chlorophenyl)-2-(trifluoromethyl)-2-oxazolin-5-one (2.5 g; 0.01 mol)
is dissolved in nitromethane (50 mL). In a single portion,
2-chloroacrylonitrile (8.0 mL; 0.10 mol) is added to the solution, and the
resulting solution is stirred 18 hours at reflux under a nitrogen
atmosphere. Cooling the red/brown solution to -5.degree. C. in an
ice-acetone bath causes the formation of a precipitate which is collected
by filtration and washed with a small portion of cold nitromethane. The
resulting tan solid is recrystallized from hot ethylene dichloride
yielding the product as white crystals (1.8 g; 56% theory), mp
238.degree.-241.degree. C. (dec.).
By utilizing the appropriate arylglycine and following the procedure of
this Example, the following
2-aryl-5-(trifluoromethyl)pyrrole-3-carbonitrile were prepared:
______________________________________
##STR38##
R L mp .degree.C.
______________________________________
H H 215-218
H 4-CH.sub.3 191-193
H 4-OCH.sub.3 168-180 (dec.)
3-Cl 4-Cl 245-246 (dec.)
H 4-CF.sub.3 218-219
______________________________________
EXAMPLE 21
Preparation of
4-Bromo-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile
Under a nitrogen purge, a suspension or
2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.6 g; 0.005
mol) in acetic acid (25 mL) is heated, all the material dissolving to a
clear solution at about 60.degree. C. A solution of bromine (0.8 mL; 0.015
mol) in acetic acid (10 mL) is added dropwise over 15 minutes to the
refluxing solution. The solution is refluxed 6 hours then allowed to stir
18 hours at room temperature. The HPLC of the reaction mixture shows about
80% conversion to product. The mixture is heated back to reflux and more
bromine (0.5 mL; 0.01 mol) in acetic acid (5 mL) is added dropwise. After
refluxing another 3 hours, the aliquot shows >95% conversion to product.
The reaction is cooled, and solvent removed under reduced pressure on a
rotary evaporator to obtain a dark grey solid. Toluene is added to the
mixture and removed under reduced pressure, but the odor of acetic acid
still remains. The entire material is dissolved in hot toluene (75 mL) to
a turbid solution which is treated with DARCO filter and filtered. The
light pink solution deposits a white solid upon cooling to ambient. After
cooling in the freezer, the solid is collected by filtration, washed with
hexanes, and dried on the filter. Further drying in a vacuum oven at
45.degree. C. provides the product (1.2 g; app. 60% theoretical); mp
247.degree.-250.degree. C.
By brominating the appropriate
2-aryl-5-(trifluoromethyl)pyrrole-3-carbonitrile, according to the above
recipe, the following additional examples are prepared:
______________________________________
##STR39##
R L mp .degree.C.
______________________________________
H H 235-238
H 4-CH.sub.3
244-245
3-Cl 4-Cl 218-223
H 4-CF.sub.3
225-226
______________________________________
APPENDIX
EXAMPLE 22
4-Chloro-3-cyano-2-(p-chlorophenyl)pyrrole
##STR40##
To a magnetically stirred 20.degree. C. solution of 17.87 g (88.2 mmol,
1.00 eq) of 2-(2-chlorophenyl)-3-cyanopyrrole in 800 mL of dioxane is
added dropwide 250.15 g (13.13 g real, 176.4 mmol, 2.00 eq) of 5.25 weight
% bleach over a period of 30 minutes. After stirring at room temperature
for a further 30 minutes, the reaction solution is poured into 2200 mL of
water. The resulting mixture is vacuum filtered to remove a small amount
of a black solid. The filtrate is acidified to pH 2 with concentrated HCl
to produce a brown solid. This solid is vacuum filtered and the collected
solids washed with water to give 22.41 g of a brown solid. This solid is
treated with 100 mL of 5% aqueous sodium hydroxide to dissolve the bulk of
the material while leaving a small amount of undissolved black solid. This
black solid, dissolved into 100 mL of ethyl acetate, is washed with 75 mL
each of 5% aqueous NAOH, water, and sat. aqueous NaCl. The ethyl acetate
layer is dried (MgSO.sub.4), treated with charcoal, filtered, and then
rotary evaporated in vacuo to give 1.10 g (5.3% yield) of an orangish
brown solid. This solid is recrystallited from an ethyl acetate chloroform
mixture to give 0.51 g (2.4% yield) of an off-white solid of
4-chloro-3-cyano-2-(p-chlorophenyl)pyrrole. mp 251.degree.-253.5.degree.
C.
EXAMPLE 23
Preparation of
5-bromo-4-chloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile
##STR41##
A sample of 5-bromo-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (0.158 g,
0.005 mole) is dissolved in tetrahydrofuran (5 mL) . An equivalent amount
of t-butyl hypochlorite is added and the solution stirred overnight. The
solution is poured into water and the precipitate (0.052 g, 30%) is
collected. The mp is >275.degree. C.
In a similiar fashion one can prepare
2-bromo-3-chloro-5-(3,4-dichlorophenyl)-4-nitropyrrole by starting with
2-bromo-5-(3,4-dichlorophenyl)-4-nitropyrrole.
EXAMPLE 24
Preparation of 5-bromo-4-chloro-2-(p-chlorophenyl)pyrrole-3-carbonitrile
##STR42##
To a magnetically stirred 22.degree. C. solution of 0.17 g (0.67 mmol.,
1.00 equivalent) of 4-chloro-2-(p-chlorophenyl)pyrrole-3-carbonitrile in
100 mL of chloroform is added dropwise over a period of 30 minutes, a
solution of 0.20 mL (0.62 g, 3.88 mol., 5.79 equivalent) of bromine in 5
mL of chloroform. The addition produces no exotherm. After stirring at
room temperature for 31/4 hours, the clear red reaction solution is
evaporated in vacuo to give 0.28 g of an off-white solid. This solid is
slurried with a hexane-methylene chloride mixture to give on vacuum
filtration 0.23 g of an off-white fluffy solid. mp 262.degree.-263.degree.
C.; dec.
EXAMPLE 25
Preparation of 5-chloro-4-bromo-2-(p-chlorophenyl)pyrrole-3-carbonitrile
##STR43##
To a magnetically stirred 45` C. solution of 1.00 g (4.22 mmol., 1.00
equivalent) of 5-chloro-2-(p-chlorophenyl)pyrrole-3-carbonitrile in 300 mL
of chloroform is added dropwise over a period of 30 minutes, a solution of
0.40 mL (1.24 g, 7.76 mmol., 1.84 equivalent) of bromine in 25 mL of
chloroform. The addition produces no exotherm and towards the end of the
addition, a small amount of a solid starts to precipitate. After stirring
at room temperature for 191/2 hours the reaction mixture is evaporated in
vacuo to give 1.49 g of an orangish white solid. This solid is slurried
with a hexane-methylene chloride mixture to give on vacuum filtration 1.33
g (100% yield) of a fluffy white solid. mp 250.degree.-258.degree. C.,
dec.
EXAMPLE 26
Preparation of 5-chloro-2-(p-chlorophenyl)pyrrole-3-carbonitrile
##STR44##
To a 35.degree. C. magnetically stirred solution of 2.40 g (11.8 mmol.,
1.00 equivalent) of 2-(p-chlorophenyl)pyrrole-3-carbonitrile, and 65 mL of
glacial acetic acid is added dropwise by syringe 0.75 mL (1.26 g, 9.34
mmol., 0.79 equivalent) of sulfuryl chloride over a period of 5 minutes.
Approximately 5 minutes after the completion of the addition, a solid
precipitated out of the reaction solution. After stirring at room
temperature for 45 minutes, the reaction mixture is filtered and the
collected solid is washed well with cold acetic acid to give 2.08 g (74%
crude yield) of an off-white solid. This solid is recrystallized from 75
mL of hot acetic acid to give 1.63 g (58% yield) of 97 wt % pure. Product
mp 258.5.degree.-261.degree. C.
EXAMPLE 27
Preparation of 2-(3,4-dichlorophenyl)-1-methylpyrrole-3-carbonitrile
##STR45##
In a 100 mL flask, 2.0 g of 2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile is
dissolved in 50 mL of dry THF and 1 equivalent of potassium t-butoxide is
added. This gives a slightly cloudy solution. One equivalent of methyl
iodide is then added to the mixture by pipette. This leads to a slight
lightening of the colour. A drying tube is attached to the flask and it is
left to stir at ambient temperature overnight.
The next morning there is a slight light-coloured precipitate in the flask.
50 mL of water is then added and the solution becomes clear before a solid
precipitates out of the solution. This solid is filtered out of the
solution and compared to the starting material by TLC (25% ethyl
acetate/hexane). This indicates a new single spot which is faster moving
than the starting material. It is dried in a vacuum oven at 50 deg. C.
overnight. The product yield is 1.31 g or 62% yield and has a melting
point of 140.degree.-142.degree. C.
EXAMPLE 28
Preparation of
4,5-dichloro-2-(3,4-dichlorophenyl)-1-methylpyrrole-3-carbonitrile
##STR46##
In a 50 mL round bottom flask, 0.5 g of
2-(3,4-dichlorophenyl)-1-methylpyrrole-3-carbonitrile is mixed with 35 mL
of glacial acetic acid. The mixture is warmed slightly with a heat gun to
dissolve all of the pyrrole.
To this clear solution is added 2 eq. of sulfuryl chloride by pipette. The
solution is left to stir at room temperature for 12 hours.
After 12 hours the solution is poured into 50 mL of water, resulting in a
white precipitate. This is filtered out and dried in a vacuum oven at
50.degree. C. for 3 hours.
The resulting solid is identical by TLC, (25% ethyl acetate/ hexane), and
infrared analysis to the product of Example 9. Product yield is 0.36
(56%).
EXAMPLE 29
Preparation of
4,5-Dichloro-2-(3,4-dichlorphenyl)-1-(2-hydroxyethyl)-pyrrole-2-carbonitri
le
##STR47##
To a stirred mixture of 2.0 g (6.5 mmol) of
4,5-dichloro-2-(3,4-dichlorophenyl)-pyrrole-3-carbonitrile and 0.88 g (7.8
mmol) of potassium tert-butoxide heated at reflux in 50 mL of dioxane is
added 0.98 g (7.8 mmol) of bromoethanol. The mixture is stirred at reflux
for 12 hours, cooled, diluted with 50 mL of water, and extracted several
times with chloroform. The combined chloroform extracts are dried over
magnesium sulfate and concentrated in vacuo to leave a solid which, on
warming and dissolving in ethyl acetate, deposits on cooling mostly
starting pyrrole. Concentration of the mother liquor and recrystallization
of the residual solid from 20% ethyl acetate in hexane gives 0.31 g of a
white solid, mp 143.degree.-145.degree. C.; IR 5077A.
Anal. Calc'd for C.sub.16 H.sub.23 NO.sub.4 ; C, 44.57, H, 2.29; N, 8.00;
Cl, 40.57. Found: (Agm 33139): C, 44.77; H, 2.29; N, 8.06; Cl, 40.14.
EXAMPLE 30
Preparation of
4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-1,3-dicarbonitrile
##STR48##
Potassium t-butoxide (617 mg, 55 mmol) is added in portions to a solution
of 3-cyano-4,5-dichloro 2-(3,4-dichlorophenyl)pyrrole (1.52 g, 5 mmol) in
anhydrous THF (20 mL). After 30 minutes, a solution of cyanogen bromide
(583 mg, 5.5 mmol) in THF (1 mL) is added. The reaction mixture is stored
at room temperature overnight. The solvent is removed in a rotary
evaporator. The residue is treated with water and extracted with ethyl
acetate. The organic layer is washed with water and saturated sodium
chloride and dried (MgSO.sub.4). Evaporation and crystallization of the
residue from ethyl acetate gives while crystals (1.07 g); mp
250.5.degree.-252.0.degree. C.; IR (nujol) 2255, 2245 cm.sup.-1 (CN);
.sup.13 C NMR (DMSO-d.sub.6) 102.7 (N--CN), 113.7 (3-CN); Mass spectrum
331.9 (M+1).
Anal. Calc'd for C.sub.12 H.sub.3 CP.sub.4 N.sub.3 (330.99) C, 43.54; H,
0.91; N, 12.70; Cl 42.85. Found: C, 4362; H, 0.93, N, 12.63; Cl 41.95.
EXAMPLE 31
Preparation of
4,5-Dichloro-2-(3,4-dichlorophenyl)-1-(3-iodo-3-pyrrole-3-carbonitrile
##STR49##
To a stirred mixture of 1.91 g (5.5 mmol) of
4,5-dichloro-2-(3,4-dichlorophenyl)-1-(2-propynyl)pyrrole-3-carbonitrile
in 500 mL of methanol is added 69 mL of 10% aqueous sodium hydroxide and
then 0.70 g (2.7 mmol) of iodine. The mixture is stirred for 12 hours and
then acidified and diluted with 200 mL of water. The precipitated solids
are collected and recrystallized from methanol to afford 0.51 g while
crystals, m.p. 115.degree.-116.degree. C.
This reaction is also applicable to the conversion of any of the formula
III, IV, V, VI or VII substituted N-alkynylarylpyrroles of the present
invention to N-substituted 3-iodo-2-propynyl arylpyrroles of said
invention.
EXAMPLE 32
Preparation of 2-(3,4-dichlorophenyl)-4,5-diiodopyrrole-3-carbonitrile
##STR50##
N-iodosuccinimide (5.7 g, 0.0254 mol,) is added slowly to a solution of
2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (3.0 g, 0.0127 mol) in 100 ml
of THF. The reaction is stirred several hours at 25.degree. C. until thin
layer chromatography (silica gel; 100:100:1-ether:petrolium ether:acetic
acid) shows completion. The mixture is evaporated in vacuo to give a
residue containing the pyrrole and succinimide. The crude solid is
dissolved in 500 mL of ether and shaken with 5.times.400 mL of water to
remove the succinimide. The ether is dried over Na.sub.2 SO.sub.4 and
evaporated in vacuo to leave 2.0 g (32.3%) of a grey-brown solid with mp
>230.degree. (loses purple vapors).
EXAMPLE 33
Preparation of 2-phenyl-1-pyrroline-4-carbonitrile
##STR51##
A solution of acrylonitrile (0.65 mL; 0.01 mol) and
N-(trimethylsilyl)methyl-S-methyl-benzenethioimidate (2.4 g; 0.01 mol) in
THF (100 mL) is cooled to -5.degree. C. in an ice-acetone bath. Under a
nitrogen purge, a solution of tetrabutylammonium fluoride (1.0 mL of a 1N
solution in THF) and THF (20 mL) is added dropwise over 30 minutes The
solution is stirred another 30 minutes at -5.degree. C., and then allowed
to warm slowly to ambient. Stirring is continued another 18 hours, and
then solvent is removed under reduced pressure. The residue is partitioned
between ether/water and the water layer extracted with fresh ether. The
combined organic layer is washed with water, then saturated sodium
chloride. The solution is dried over MgSO.sub.4, and cooling the filtrate
causes precipitation of an off-white solid (1.2 g; 70% theoretical yield)
whose spectral characteristics are identical to the material described by
Tsuge [J. Org. Chem. 52, 2523 (1987)].
Calcd. for C.sub.11 H.sub.10 N.sub.2 : C, 77.65; H, 5.88; N, 16.47. Found:
C, 77.55; Hg 5.83; N, 16.39. mp=95.degree.-97.degree. C.
EXAMPLE34
Preparation of 2-phenyl-pyrrole-4-carbonitrile
##STR52##
Under a nitrogen purge 2,3-dichloro-5,6-dicyano-1,4-bonzoquinone (0.23 g;
0.001 mol) and 2-phenyl-1-pyrroline-4-carbonitrile (0.17 g; 0.001 mol) is
dissolved in 1,2-dimethoxyethane (13 mL) to form a clear orange solution.
Pyridine (0.08 mL; 0,001 mol) is added in a single portion, causing a
slight exotherm (to ca. 28.degree. C.) and an immediate formation of a
green/grey precipitate. The suspension is stirred at room temperature for
18 hours during which time much of the solvent evaporates. The brownish
semi-solid residue is partitioned between ether and a half-saturated
solution of sodium carbonate. The red-brown aqueous layer is extracted
twice with ether and the combined ether layer is washed with fresh water,
then saturated sodium chloride. After drying with MgSO.sub.4, solvent is
removed under reduced pressure to obtain a white semi-solid. This material
was recrystallized from ethylene dichloride (DARCO treatment) to yield
lavender crystals (0.1 g).
The identical product is obtained directly in a single step by condensing
.alpha.-chloroacrylonitrile and
N-(trimethylsilyl)methyl-S-methyl-benzenethioimidate using
tetrabutylammonium fluoride catalysis (analogous to the preparation of
2-phenyl-1-pyrroline-4-carbonitrile described previously).
Calcd. for C.sub.11 H.sub.8 N.sub.2 : C, 78.57, H, 4.76; N, 16.67. Found:
C. 78.65; H, 4.70; N, 16.43. m.p.--155.degree.-158.degree. C.
EXAMPLE 35
Preparation of 2,4-dibromo-5-phenyl pyrrole-3-carbonitrile
##STR53##
Under a nitrogen purge, a solution of bromine (0.6 mL; 0.012 mol) in
CHCl.sub.3 (5 mL) is added dropwise over 20 minutes to a stirring solution
of 2-phenyl-pyrrole-4-carbonitrile (0.84 g; 0.05 mol) in CHCl.sub.3, (20
mL). The resulting solution is stirred 18 hours at room temperature, then
solvent is removed under reduced pressure to obtain a solid which is
recrystallized from C.sub.2 H.sub.4 Cl.sub.2 (DARCO treatment), yielding
the desired final product (0.6 g), m.p.=239.degree.-242.degree. C.
Calcd. for C.sub.11 H.sub.6 Br.sub.2 N.sub.2 : C, 40.49; H, 1.84; Br,
49.08; N, 8.59. Found: C, 39.88; H, 1.87; Br, 48.81; N, 8.48.
By the procedure described in Example 24, 25 and 26,
2,4-dibromo-5-(p-chlorophenyl)pyrrole-3-carbonitrile, mp.
270.degree.-272.degree. C. (dec.) is also prepared.
EXAMPLE 36
3',4'-Dichloro-3-(1,3-dioxolan-2-yl)-propiophenone
##STR54##
To a rapidly stirring mixture of magnesium turnings (0.64 g, 26 mmol) in 10
mL of tetrahydrofuran at 25.degree. C. in a 100 mL three-neck round bottom
flask equipped with a thermometer, a 60 mL addition funnel, and a nitrogen
inlet is added dropwise 2-(2-bromoethyl)-1,3-dioxolane (4.7 g, 26 mmol) in
40 mL of tetrahydrofuran. The rate of addition is adjusted so as to
maintain the reaction temperature below 50.degree. C. The reaction is then
allowed to stir for 1 hour at 25.degree. C. 120 mL of tetrahydrofuran is
mixed with potassium 3,4-dichlorobenzoate (5.0 g, 22 mmol) under a blanket
of nitrogen. The Grignard solution is then quickly decanted away from the
unreacted magnesium turnings, and added dropwise to the rapidly stirring
potassium benzoate suspension. The reaction is then allowed to stir for 24
hours at 25.degree. C. Fifty mL of diethyl ether and 15 mL of 3N
hydrochloric acid are added to the reaction mixture and the layers
separated. The organic layer is washed with saturated aqueous sodium
bicarbonate until neutral followed by one washing with 10 mL of brine.
Drying over sodium sulfate, and rotary evaporation yields a beige
semisolid which is chromatographed over silica gel using 3:1 hexane-ethyl
acetate as eluent to give the keto-acetal (4.3 g, 60%) as a white solid,
m.p. 115.degree.-117.degree. C.
EXAMPLE 37
Preparation of 3-(3,4-dichlorobenzoyl)propionaldehyde
##STR55##
Ten grams (26 mmol) of 3',4'-dichloro-3-(1,3-dioxolan-2-yl)-propiophenone
is added to 30 mL of 0.2M oxalic acid (made by dissolving 0.9 g of oxalic
acid dehydrate in 30 mL of water) and 5 mL of ethanol. The mixture is
refluxed for 1 hour and then allowed to cool. Most of the ethanol is
rotary evaporated off and 100 mL of diethyl ether is added along with 20
mL of saturated aqueous sodium bicarbonate. The layers are separated and
the organic phase is dried over magnesium sulfate. Rotary evaporation
yields a viscous yellow oil which is chromatographed over silica gel using
3:1 hexane-ethyl acetate to give the keto-aldehyde (6.3 g, 75%) as a white
solid.
EXAMPLE 38
Preparation of 2-(3,4-dichlorophenyl)pyrrole
##STR56##
To a suspension of 3-(3,4-dichlorobenzoyl) propionaldehyde (6 g, 26 mmol)
in 60 mL of absolute ethanol is added ammonium acetate (4 g, 52 mmol). The
reaction is refluxed for 20 minutes and allowed to cool. Most of the
ethanol is rotary evaporated and 200 mL of 1:1 dichloromethane-diethyl
ether along with 50 mL of water is added. The layers are separated and the
organic phase is dried over sodium sulfate. Rotary evaporation yields a
dark brown oil which is chromatographed over silica gel using 3:1
hexane-ethyl acetate as eluent to give the pyrrole (4.6 g, 83%) as a light
brown solid, m.p. 49.degree.-51.degree. C.
EXAMPLE 39
Preparation of 5-(3,4-dichlorophenyl)pyrrole-2-carboxaldehyde
##STR57##
To 10 mL of dimethylformamide stirring under nitrogen in a 50 mL round
bottom flask is added phosphorus oxychloride (0.6 mL, 6.5 mmol) dropwise
via syringe. The solution, warms and becomes light yellow in color. It is
allowed to stir for 20 minutes before the portionwise addition of
2-(3,4-dichlorophenyl)pyrrole (1 g, 4.7 mmol) . The beige suspension which
results is allowed to stir for 30 minutes before being heated to
50.degree. C. for 40 minutes. A solution of sodium acetate (10 g, 122
mmol) in 15 mL of water is added to the cooled reaction which is then
allowed to stir for 20 minutes. A beige precipitate is filtered off from
the reaction mixture and air-dried for 20 hours to give the essentially
pure aldehyde (1.1 g, 95%), mp >200.degree. C.
EXAMPLE 40
Preparation of 5-(3,4-dichlorophenyl)pyrrole-2-carbonitrile
##STR58##
To a suspension of 5-(3,4-dichlorophenyl)pyrrole-2-carboxaldehyde (1.5 g,
6.2 mmol) in 20 mL of water and 20 mL of ethanol, is added
hydroxylamine-O-sulfonic acid (0.7 g, 6.2 mmol). The reaction is refluxed
for 1 hour during which time a gray precipitate appears. After being
allowed to cool, the reaction is filtered to give essentially pure nitrile
(1.5 g, 99%) as a gray solid, m.p. 170.degree.-171.degree. C.
EXAMPLE 41
Preparation of 3,4-dibromo-5-(3,4-dichlorophenyl)pyrrole-2-carbonitrile
##STR59##
To a solution of 5-(3,4-dichlorophenyl)pyrrole-2-carbonitrile (0.5 g, 2.1
mmol) in 20 mL of tetrahydrofuran under nitrogen is added portionwise
N-bromo-succinimide (0.8 g, 4.2 mmol). The reaction is stirred at
25.degree. C. for 30 minutes before the addition of 10 mL of water and 40
mL of diethyl ether. The layers are separated and the organic layer dried
over sodium sulfate. Rotary evaporation is followed by chromatography over
silica gel using 3:1 hexane-ethyl acetate as eluent to afford the
dibromopyrrole (0.5 g, 60%) as a brown solid, m.p. >250.degree. C.
EXAMPLE 42
Preparation of 4-phenylpyrrole-3-carbonitrile
##STR60##
To a mixture of 5.0 g (39 mmol) of cinnamonitrile and 7.6 g (39 mmol) of
(p-tolylsulfonyl)methyl isocyanide in 35 mL of DMSO and 65 mL of ether is
added over a 20 minute period a suspension of 1.86 g of a 60% oil
suspension of sodium hydride (1.11 g; 46 mmol) in 80 mL of ether. The
reaction mixture is maintained under nitrogen for an hour and then diluted
with ether and water. The ether layer is separated, dried over magnesium
sulfate, and concentrated in vacuo. The resulting oil is chromatographed
on silica gel using 1:1 chloroform ethyl acetate to give 2.5 g of
cream-colored solids. Recrystallization from ether-hexane affords 1.15 g,
m.p. 123.degree.-125.degree. C.; NMR M86-1077.
Lit.: Tet. Letters 5337 (1972): m.p. 128.degree.-129.degree. C.
EXAMPLE 43
Preparation of 2,5-dichloro-4-phenylpyrrole-3-carbonitrile
##STR61##
To a stirred mixture of 0.66 g (3.9 mmol) of 4-phenylpyrrole-3-carbonitrile
in 20 mL of dry THF cooled to 6.degree. C. with an ice-water bath is added
from a syringe 0.66 mL (1.11 g; 8.2 mmol) of sulfuryl chloride over a 4
minute period. The mixture is maintained at 5.degree.-10.degree. C. for an
additional 45 minutes and then stirred an additional 30 minutes with the
ice bath removed. After the reaction mixture is poured into 80 mL of ethyl
acetate and 40 mL of water, the organic phase is separated, washed with
water, and dried over sodium sulfate. Filtration through a short column of
silica gel, rinsing with ethyl acetate, and concentration of the combined
filtrated in vacuo gives 0.95 g of dark solid. Recrystallization from
chloroform gives 0.42 g of off-white crystals, m.p.
195.degree.-196.degree. C. (dec.).
Anal. Calcd for C.sub.11 H.sub.6 Cl.sub.2 N.sub.2 : C, 55.72; H; 2.55; N,
11.82; Cl, 29.91. Found: C, 55.66; H, 2.65; N, 11.69; Cl, 29.97.
Following the procedures of Examples 33 and 34, the following analogs are
prepared. For the synthesis of
2,6-dibromo-4-(p-chlorophenyl)pyrrole-3-carbonitrile, the procedure of
Example 33 is followed using bromine in dioxane to replace sulfuryl
chloride and tetrahydrofuron.
______________________________________
##STR62##
R X Y mp .degree.C.
______________________________________
4-Cl Cl Cl 237-240 (dec.)
4-CH.sub.3 Cl Cl 103-206
4-Cl Br Br >245.degree.
______________________________________
EXAMPLE 44
Ethyl 4-(p-chlorophenyl)-pyrrole-3-carboxylate
##STR63##
To a mixture of 5.63 g of a 60% sodium hydride/oil suspension in 200 mL of
dry ether under nitrogen is added from an additional funnel a mixture of
23.5 g (122 mmol) of ethyl p-chlorocinnamate and 19.4 g (122 mmol) of
(p-tolylsulfonyl)methyl isocyanide in solution in 180 mL of ether and 80
mL of dimethylsulfonide. The addition time is about 20 minutes and results
in gentle refluxing of the mixture. After another 10 minutes stirring, the
mixture is diluted with 100 mL of water. The mixture is extracted four
times with ether which is then dried over magnessium sulfate followed by
concentrated in vacuo. The resulting solid is recrystallized from ethylene
dichlorite to give 7.8 g of crystals, m.p. 137.degree.-138.degree. C.
Anal. Calcd for C.sub.13 H.sub.12 ClNO.sub.2 : C, 62.53; H, 4.81; N, 5.61;
Cl, 14.23. Found: C, 61.31, H, 5.12; N, 5.32; Cl, 14.57.
Concentration of the mother liquor for the crystallization leaves
additional crude ester which is carried on to the saponification step.
EXAMPLE 45
Preparation of 3-(p-chlorophenyl)-pyrrole
##STR64##
A mixture of 22.0 g of crude ethyl 4-(p-chlorophenyl)-pyrrole-3-carboxylate
from the recrystallization mother liquor and the recrystallized product
from the previous step is stirred at reflux with 150 mL of 10% aqueous
sodium hydroxide for 2.5 hours. The mixture is cooled, extracted with
ether, and acidified to give a precipitate which on collection and drying
weighs 11.6 g.
A mixture of 10.5 g of the acid in 100 mL of .beta.-ethanolanine is heated
at reflux for three hours. After cooling, the mixture is poured over 400
mL of ice and the resulting mixture is extracted four times with
chloroform. The chloroform solution, after drying over magnesium sulfate
and treatment with activated charcoal, is concentrated in vacuo to leave a
brown solid. Chromatography on silica gel using 1:1 ethyl acetate hexane
gives 4.0 g of a white solid,, m.p. 117.degree.-118.degree. C.
EXAMPLE 46
Preparation of 3-(p-chlorophenyl)-pyrrole-2-carboxaldehyde
##STR65##
To a mixture of 0.86 g (12 mmol) of dimethylformamide in 10 mL of ethylene
dichloride maintained under nitrogen and cooled in an ice bath is added
1.49 g (12 mmol) of oxalyl chloride in 10 mL of ethylene dichloride over a
period of 25 minutes. The ice bath is removed, the mixture is stirred an
additional 15 minutes and recooled in an ice bath. To this mixture is
added 1.5 g (8.5 mmol) of 3-(p-chlorophenyl)-pyrrole in 25 mL of ethylene
dichloride over a 20 minute period. The ice bath is removed and after an
additional 30 minutes of stirring, the mixture is poured into 50 mL of
ice-water and 6 mL of 50% sodium hydroxide. The resulting mixture is
extracted with ether and with chloroform and the combined organic mixture
is dried over magnesium sulfate and concentrated in vacuo. Purification of
the resulting solid by chromatography on silica gel using 1:1 ethyl
acetate hexane gives 0.63 g of off-white solid which is used directly for
conversion to 3-(p-chlorophenyl)-pyrrole-2-carbonitrile,
EXAMPLE 47
Preparation of 3-(p-chlorophenyl)-pyrrole-2-carbonitrile
##STR66##
A mixture of 0.63 g (3.1 mmol) of
3-(p-chlorophenyl)-pyrrole-2-carboxaldehyde in 10 mL of water is stirred
and ice-cooled while 0.52 g (4.6 mmol) of hydroxylamine-o-sulfonic acid in
10 mL of water is slowly added. After the addition, the cooling bath is
removed and the mixture is heated for 25 minutes. On cooling, the
resulting solid is collected and shown, by NMR, to be a mixture of product
and starting aldehyde. This mixture is reacted in the same manner with an
additional 0.49 g (4.2 mmol) of hydroxylamine-O-sulfonic acid in a total
of 30 mL of water. The mixture is heated at 60.degree.-70.degree. C. for 2
hours. The mixture is cooled and the resulting solids are collected and
purified by chromatography or silica gel using 1:1 ethyl acetate hexane to
give 0.40 g of pink solid, m.p. 114.degree.-115.degree. C.
EXAMPLE 48
Preparation of 4,5-Dibromo-3-(p-chlorophenyl)-pyrrole-2-carbonitrile
##STR67##
To a mixture 0.40 g (2.0 mmol) of 3-(p-chlorophenylpyrrole)-2-carbonitrile
in 25 mL of chloroform is added 0.63 g (4.0 mmol) of bromine. After 20
minutes, the precipitate which forms is collected and recrystallized from
ethyl acetate to give 0.21 g of pink crystals, m.p. >250.degree. C.
Anal. Calcd for C.sub.11 H.sub.5 Br.sub.2 ClN: C; 36.62; H, 1.39; Br,
44.38; Cl, 9.85; N, 7.77. Found: C, 36.92; H, 1.32; Br, 44.62; Cl, 9.88;
N, 7.50.
EXAMPLE 49
Preparation of Ethyl 5-bromo-4-(p-chlorophenyl)pyrrole-3-carboxylate
##STR68##
Ethyl 4-(p-chlorophenyl)pyrrole-3-carboxylate (1.6 g., 0.0064 mmol) is
dissolved in tetrahydrofuran (40 mL). N-bromosuccinimide (1.14 g., 0.0064
mmol) is added in small portions at 25.degree.-28.degree. C. After the
addition is complete, the solution is stirred overnight at room
temperature. The solution is concentrated in vacuo and the solid residue
partioned between water and ether. The ether layer is separated and dried
over magnesium sulfate. Work-up of the ether extract leaves 1.9 g (90%) of
a white solid which is purified by stirring with a mixture of 80/20
hexane/ethyl acetate. The insoluble solid (1.3 g, 62%) is collected and
has m.p. 161.degree.-164.degree. C.
Calcd for C.sub.13 H.sub.11 BrClNO.sub.2 : C, 47.50; H, 3.34; N,, 4.26; Br,
24.33; Cl; 10.80. Found: C, 47.39; H, 3.38; N, 4.12; Br, 24.29; Cl, 10.77.
EXAMPLE 50
Preparation of 5-bromo-4-(p-chlorophenyl)pyrrole-3-carboxylic acid
##STR69##
Ethyl 5-bromo-4-(p-chlorophenyl)pyrrole-3-carboxylate (15 g., 0.045 mmol)
is added to 200 mL of 10% sodium hydroxide and the slurry heated to
reflux. After everything appears to dissolve the mixture is refluxed an
additional 40 minutes. The mixture is cooled, filtered and the filtrate
acidified. The white precipitate (8.0 g,, 58%) is collected and dried. The
solid has m.p. >205.degree. C. and an NMR (d.sub.6 -DMSO) which showed a
pyrrole proton at 7.52 (d). The mass spectrum is also consistent for a
monobrominated compound.
EXAMPLE 51
Preparation of 2-bromo-3-(p-chlorophenyl)pyrrole
##STR70##
5-bromo-4-(p-chlorophenyl)pyrrole-3-carboxylic acid (8.0 g., 0.026 mmol) is
added to aminoethanol (24 mL) and the slurry slowly warmed to
110.degree.-120.degree. C. and held at that temperature for 1 hour. The
solution is cooled and poured into water and extracted with ether. The
ether extract, by thin layer chromatography (75/25, hexane/ethyl acetate),
shows a major fast moving spot and a slower moving minor component.
Work-up of the ether leaves a dark solid (4.0 g., 56%) which is
2-bromo-3-(p-chlorophenyl)pyrrole and is used immediately to prepare
5-bromo-4-(p-chlorophenyl)pyrrole-2-carbonitrile.
EXAMPLE 52
Preparation of 5-bromo-4-(p-chlorophenyl)pyrrole-2-carbonitrile
##STR71##
A freshly prepared sample of 2-bromo-3-(p-chlorophenyl)pyrrole (4.0 g.,
0.015 mmol) is dissolved in dry dimethoxyethane (25 mL). Then while
holding the temperature below 25.degree. C., chlorosulfonyl isocyanate
(3.08 g., 0.022 mmol) is added. After stirring overnight, the solution is
treated with dimethylformamide (6 mL) and stirred for 3 hours. Finally,
the solution is poured into water precipitating a brown solid (3.8 g,
90%). Dry column chromatography (80/20 hexane/ethyl acetate) yields 1.4 g
(33%) of white solid with m.p. 202.degree.-204.degree. C.
Calcd for C.sub.11 H.sub.6 BrClN.sub.2 : C, 46.90; H, 2.13; N; 9.95; Cl,
12.61; Br, 28.39. Found: C, 47.20; H, 2.09;,N, 9.80; Cl, 12.36; Br, 27.42.
EXAMPLE 53
Preparation of 3,5-Dibromo-4-(p-chlorophenyl)pyrrole-2-carbonitrile
##STR72##
A sample of 5-bromo-4-(p-chlorophenyl)pyrrole-2-carbonitrile (2.2 g.,
0.0078 mol) is dissolved in 30 mL of dry dioxane. The solution is heated
with bromine (1.3 g., 0.008 mol) in dioxane (20 mL) and then stirred
overnight at room temperature. The reaction mixture is poured into water
precipitating a tan solid (2.6 g., 92%). A portion (1.6 g) is purified by
flash chromatography using 75/25 hexane/ethyl acetate to give 0.8 g of
grey solid with m.p. 191.degree.-194.degree. C.
Calcd for C.sub.11 H.sub.5 Br.sub.2 ClN.sub.2 : C, 36.61; H, 1.38; N, 7.76;
Cl, 9.84; Br, 44.3. Found: C, 37.46; H, 1.25; N, 7.41; Cl, 9.53; Br,
42.99.
EXAMPLE 54
Preparation of 3-(3,4-dichlorophenyl)-4-nitropyrrole
##STR73##
Sodium hydride (2.66 g of a 60% suspension in oil is rinsed with dry ether;
66 mmol) and suspended in 150 mL of dry ether. To this mixture is added
over 15 minutes a mixture of 12.0 g (5.5 mmol) of
3,4-dichloro-.beta.-nitrostyrene and 10.8 g (5.5 mmol) of
(p-tolylsulfonyl)methyl isocyanide in 50 mL of DMSO and 150 mL of ether.
The mixture is stirred for 1.5 hours and then diluted with 150-200 mL of
water and additional ether. The ether layer is separated, dried over
magnesium sulfate, and concentrated in vacuo. The resulting 10.6 g of
crude product is purified by chromatography on silica gel using a 4:1
mixture of chloroform and ethyl acetate. A 7.2 g solid fraction is
recrystallized from chloroform-ethyl acetate-hexane to give 3.0 g of
yellow solid, m.p. 187.degree.-188.degree. C. (dec.).
Anal. Calcd for C.sub.10 H.sub.6 Cl.sub.2 N.sub.2 O.sub.2 : C, 46.72; H;
2.35; N, 10.90. Found: C, 46.96; H, 2.60; N, 9.77.
EXAMPLE 55
Preparation of 2,5-Dichloro-3-(3,4-dichlorophenyl)-4-nitropyrrole
##STR74##
To a mixture of 3-(3,4-dichlorophenyl)-4-nitropyrrole (2.5 g, 9.7 mmol)
warmed to about 40.degree. C. in 200 mL of chloroform is added over one
minute 2.95 g (22 mmol) of sulfuryl chloride. After another hour, the
mixture is diluted with 100 mL of saturated sodium bicarbonate solution
and 300 mL of ether. The organic layer is separated and dried over
magnesium sulfate. Concentration, in vacuo, leaves a brown solid which is
chromatographed on silica gel using 4:1 chloroform ethyl acetate. An
orange solid fraction is recrystallized from chloroform and then
rechromagraphed on silica gel using 4:1 chloroform ethyl acetate to yield
0.36 g of yellow solid, m.p. 193.degree.-194.degree. C.
Also prepared by procedure of Examples 45 and 46 above is
2,5-dichloro-3-nitro-4-phenylpyrrole, m.p. 193.degree.-194.degree. C.
(dec.).
EXAMPLE 56
Preparation of 3-Bromo-5-(p-chlorophenyl)pyrrole-2,4-dicarbonitrile
##STR75##
A sample of 5-(p-chlorophenyl)pyrrole-2,4-dicarbonitrile (1.0 g, 0.004
mole) is dissolved in 20 mL of dioxane and-a solution of bromine (0.8 g,
0.005 mole) in dioxane (10 mL) is then added thereto. The solution is
stirred several hours at room temperature and then poured into water
precipitating a white solid (1.2 g, 100%). The solid has a m.p.
>225.degree. C. and a mass spectrum of a sample gives a pattern consistent
with the desired structure.
Following the procedure set forth above in Example 48, the following
additional compounds are prepared:
______________________________________
##STR76##
R L m.p.
______________________________________
3-Cl 4-Cl >250.degree. C.
H 4-OCF.sub.3
218-223.degree. C.
H 4-CF.sub.3
239-241.degree. C.
______________________________________
EXAMPLE57
Preparation of bromofumaronitrile
##STR77##
Under a nitrogen purge, fumaronitrile (15.6 g; 0.2 mol) in CHCl.sub.3 (150
mL) is heated to reflux, resulting in a clear solution. A solution of
bromine (5.3 mL; 0.2 mol) in CHCl.sub.3 (25 mL) is added dropwise over 30
minutes, resulting in a slow decolorization and acidic (pH test paper)
fumes being released. The solution is refluxed another 90 minutes, during
which time most of the color has been discharged. The solution is cooled
and solvent is removed under reduced pressure, leaving an amber oil
(weight approximately theoretical for bromofumaronitrile). The oil is
subjected to bulb-to-bulb distillation (0.2 mm Hg), maintaining the
temperature below 120.degree. C. (above that point, a rapid decomposition
of material occurs). A semi-solid is obtained which slowly forms a waxy,
amber solid, m.p. -43.degree.-47.degree. C.
Calcd for C.sub.4 HBRN: C, 30.57; He 0.64; Ne 17.83. Found: C, 29.13; H,
0.75; N; 16.94.
EXAMPLE 58
Preparation of 2-phenyl-pyrrole-3,4-dicarbonitrile
##STR78##
Under a nitrogen purge, a solution of bromofumaronitrile (4.7 g; 0.03 mol)
and N-(trimethylsilyl) methyl-S-methyl-benzene-thioimidate (7.1 g; 0.03
mol) in hexamethylphosphoramide (HMPA) (35 mL) is stirred at room
temperature. In a single portion, water (1.6 mL); 0.09 mol) is added,
washed in with HMPA (10 mL) . The solution almost immediately begins to
exotherm, the temperature rapidly reaching 100.degree. C. before
subsiding. The resulting dark red solution in allowed to stir at ambient
temperature 20 hours. Pouring the reaction mixture onto an ice/water
mixture results in a gummy material which slowly yields a discreet beige
solid. This material is collected by filtration and washed with cold water
and dried on the filter. After further drying (vacuum oven; 60.degree.
C.), the material is twice recrystallized from C.sub.2 H.sub.4 Cl.sub.2
(DARCO treatment) to yield a white powder.
Calcd for C.sub.12 H.sub.7 N.sub.3 : C, 74.61; H, 3.63; N, 21.76. Found: C,
74.45; H, 3.84; N, 21.61. m.p.=197.degree.-200.degree. C.
EXAMPLE 59
Preparation of 2-bromo-5-phenylpyrrole-3,4-dicarbonitrile
##STR79##
Under a nitrogen purge, 2-phenyl-pyrrole-3,4-dicarbonitrile (1.4 g; 0.0075
mol) is added to CHCl.sub.3 (35 mL), much of the solid dissolving. A
solution of bromine (0.4 mL; 0.008 mol) in CHCl.sub.3 (5 mL) is added
dropwise over 20 minutes. Initially the color is discharged rapidly, but
as a new, gummy solid begins to precipitate, the color remains. After
stirring 30 minutes at ambient, the mixture is brought to reflux,
resulting in a much more discreet solid. After refluxing 90 minutes, the
reaction mixture is cooled and an aliquot is removed and analyzed (HPLC),
showing ca. 60% starting material still remaining. In a single portion
fresh bromine (0.2 mL; 0.004 mol) is added, and refluxing continued
another 45 minutes whereupon an aliquot shows 10% starting material
remaining. Another fresh portion of bromine (0.2 mL; 0.004 mol) is added
to the refluxing suspension and refluxing is continued another 30 minutes.
The suspension is cooled and stirred 18 hours at room temperature. Solvent
is removed under reduced pressure to yield a greenish solid which is
extracted with hot CHCl.sub.3, leaving behind a dark residue. The extract
is treated with DARCO and filtered hot. The clear yellow filtrate quickly
began to deposit a white precipitate. After cooling to -10.degree. C., the
white solid is collected by filtration.
Calcd for C.sub.12 H.sub.6 BrN.sub.3 : C, 52.94; H, 2.21; N, 15.44; Br,
29.41.
Found: C, 51.64; H, 2.35; N, 14.91; Br, 28.69. m.p.=225.degree.-258.degree.
C.
EXAMPLE 60
Preparation of 2-(3,4-Dichlorophenyl)-5-nitropyrrole-3-carbonitrile
##STR80##
2-(3,4,-Dichlorophenyl)pyrrole-3-carbonitrile (3.0 g, 0.013 mole) is added
to acetic anhydride (50 mL) and 90% nitric acid (0.6 ml) with very little
exotherm. The mixture is slowly warmed to 30.degree. and is then held at
30.degree.-33.degree. until everything goes into solution. Gradually a new
solid precipitates. The mixture is stirred for 2 to 3 hours at room
temperature and then poured into water and ice to decompose the acetic
anhydride. After stirring 1 hour the mixture is filtered and the solid
(2.9 g, 82%) collected and dried. A portion (1.5 g) is purified by column
chromatography on silica gel using 75/25 hexane/ethyl acetate for elution
to give 0.7 g of yellow solid with m.p. 228.degree.-231.degree..
Calcd for C.sub.11 H.sub.5 Cl.sub.2 N.sub.3 O.sub.2 : C, 46.80; H, 1.77; N,
14.89; Cl, 25.17. Found: C, 46.50; N, 1.96; N, 14.27; Cl, 24.30.
By the same procedure, starting with
2-(p-chlorophenyl)pyrrole-3-carbonitrile,
2-(p-chlorophenyl)-5-nitropyrrole-3-carbonitrile is obtained, m.p.
201.degree.-206.degree. C. Also,
2-(p-trifluoromethylphenyl)pyrrole-3-carbonitrile gives
2-(p-trifluoromethylphenyl)-5-nitropyrrole-3-carbonitrile by the above
procedure. This compound has a melting point of 164.degree.-165.5.degree.
C.
EXAMPLE 61
Preparation of 4-Bromo-2-(3,4-dichlorophenyl-5-nitropyrrole-3-carbonitrile
##STR81##
2-(3,4-Dichlorophenyl)-5-nitropyrrole-3-carbonitrile (0.5 g, 0.0017 mol) is
dissolved in dry dioxane (10 mL) . To this solution is added bromine (0.28
g, 0.0017 mole) in dioxane. After stirring overnight, the solution is
poured into water precipitating a tan solid (0.54 g, 88%).
Recrystallization from acetonitrile (5 mL) gives 0.26 g of tan solid with
m.p. 195.degree.-200.degree. C.
Calcd for C.sub.11 H.sub.4 BrCl.sub.2 N.sub.3 O.sub.2 : C, 36.57; H, 1.10;
N, 11.63; Br, 22.13; Cl, 19.67. Found: C, 36.46; H, 1.29; N, 11.50; Br,
21.63; Cl, 19.28.
Following the above procedure of Example 53, but starting with
2-(p-chlorophenyl)-5-nitropyrrole-3-carbonitrile gives
4-bromo-2-(p-chlorophenyl)-5-nitropyrrole-3-carbonitrile, m.p.
180.degree.-185.degree. C.
EXAMPLE 62
5(3,4-Dichlorophenyl)-4-nitropyrrole-2-carbonitrile
##STR82##
To a suspension of 5-(3,4-dichlorophenyl)pyrrole-2-carbonitrile (1.2 g, 5.1
mmol) in 25 mL of acetic anhydride at 300 under nitrogen, is added
dropwise 90% nitric acid (0.3 mL, 5.1 mmol). The reaction exotherms to
45.degree. C. and becomes a green solution. After being allowed to stir
for 2 hours the reaction is poured into 50 mL of water and stirred
vigorously for 5 minutes. The beige precipitate which results is filtered
off and dissolved in a minimum amount of acetone. Chromatography over
silica gel using 3:1 hexane-ethyl acetate affords the nitropyrrole (1.2 g,
84%) as an off-white solid, m.p. >200.degree. C.
EXAMPLE 63
3-Bromo-5-(3,4-dichlorophenyl)-4-nitropyrrole-2-carbonitrile
##STR83##
To a suspension of 5-(3,4-dichlorophenyl)-4-nitropyrrole-2-carbonitrile
(0.6 g, 2.1 mmol) in 10 mL of dioxane at 25.degree. C., under nitrogen, is
added dropwise a solution of bromine (0.3 g, 2.1 mmol) in 5 mL of dioxane.
The reaction is allowed to stir overnight. Addition of 50 mL of water
causes precipitation of a yellow solid which is collected and vacuum oven
dried (50 mm Hg, 45.degree. C.) to afford the brominated pyrrole (0.7 g,
90%) as a light yellow solid, m.p. >200.degree. C.
EXAMPLE 64
4-(p-chlorophenyl)-2-(trifluoromethyl-2-oxazolin-5-one
In a single portion, trifluoroacetic anhydride, (1.7 mL; 0.012 mol) is
added to powdered 2-(p-chlorophenyl)glycine (11.4 g; 0.06 mol), causing an
immediate exotherm to about 40.degree. C., a yellow color forming on the
surface of the solid. As the mixture is slowly heated to 70.degree. C.,
more of the solid dissolves to an orange/amber oil. All the solid
dissolved in approximately 2 hours, and heating is continued another hour.
Solvent is removed under reduced pressure on a rotary evaporator. Toluene
is twice added and removed under reduced pressure, but the odor of
trifluoroacetic acid is still evident. This yellow semi-solid (yield
theoretical; purity >90% by HPLC) is the above-identified compound and is
used in the next step without further purification.
EXAMPLE 65
Preparation of
2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3,4-dicarbonitrile
##STR84##
Trifluoroacetic anhydride (3.1 mL; 0.022 mol) is added in a single portion
to (4-chlorophenyl)glycine (2.0 g; 0.011 mol), causing an immediate yellow
color and some refluxing. The mixture is slowly heated to reflux, causing
all the material to dissolve to a yellow/orange solution which is heated 2
hours further. The reaction mixture is cooled, and solvent removed under
reduced pressure. Toluene, is twice added and removed under reduced
pressure to yield a very thick oil (V.sub.CO =1800 cm.sup.-1). This
residue is dissolved (some insolubles) in CH.sub.3 NO.sub.2 (40 mL) and
bromofumaronitrile (2.7 g; 0.018 mol) is added in a single portion. The
resulting solution is heated at reflux 18 hours, yielding a dark red
solution. Solvent is removed under reduced pressure and the dark residue
is dissolved in CH.sub.2 Cl.sub.2, some insolubles being removed by
filtration. The material is fractionated via dry column chromatography
(silica gel; 3% 2-PrOH in CH.sub.2 Cl.sub.2), and appropriate fractions
are taken. Evaporation of one fraction yields the desired compound as a
yellow solid which is recrystallized from CH.sub.3 CN (DARCO treatment) to
yield a pale yellow solid (0.2 g). m.p.=238.degree.-241.degree. C. (some
dec).
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